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19 25 IL-17A protein Inhibiting complex IL-17A and IL-17RA interactions with a linear peptide TITLE |
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30 37 IL-17RA protein Inhibiting complex IL-17A and IL-17RA interactions with a linear peptide TITLE |
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65 72 peptide chemical Inhibiting complex IL-17A and IL-17RA interactions with a linear peptide TITLE |
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0 6 IL-17A protein IL-17A is a pro-inflammatory cytokine that has been implicated in autoimmune and inflammatory diseases. ABSTRACT |
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29 37 cytokine protein_type IL-17A is a pro-inflammatory cytokine that has been implicated in autoimmune and inflammatory diseases. ABSTRACT |
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11 21 antibodies protein_type Monoclonal antibodies inhibiting IL-17A signaling have demonstrated remarkable efficacy, but an oral therapy is still lacking. ABSTRACT |
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33 39 IL-17A protein Monoclonal antibodies inhibiting IL-17A signaling have demonstrated remarkable efficacy, but an oral therapy is still lacking. ABSTRACT |
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2 41 high affinity IL-17A peptide antagonist chemical A high affinity IL-17A peptide antagonist (HAP) of 15 residues was identified through phage-display screening followed by saturation mutagenesis optimization and amino acid substitutions. ABSTRACT |
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43 46 HAP chemical A high affinity IL-17A peptide antagonist (HAP) of 15 residues was identified through phage-display screening followed by saturation mutagenesis optimization and amino acid substitutions. ABSTRACT |
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51 62 15 residues residue_range A high affinity IL-17A peptide antagonist (HAP) of 15 residues was identified through phage-display screening followed by saturation mutagenesis optimization and amino acid substitutions. ABSTRACT |
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86 109 phage-display screening experimental_method A high affinity IL-17A peptide antagonist (HAP) of 15 residues was identified through phage-display screening followed by saturation mutagenesis optimization and amino acid substitutions. ABSTRACT |
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122 157 saturation mutagenesis optimization experimental_method A high affinity IL-17A peptide antagonist (HAP) of 15 residues was identified through phage-display screening followed by saturation mutagenesis optimization and amino acid substitutions. ABSTRACT |
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162 186 amino acid substitutions experimental_method A high affinity IL-17A peptide antagonist (HAP) of 15 residues was identified through phage-display screening followed by saturation mutagenesis optimization and amino acid substitutions. ABSTRACT |
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0 3 HAP chemical HAP binds specifically to IL-17A and inhibits the interaction of the cytokine with its receptor, IL-17RA. ABSTRACT |
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26 32 IL-17A protein HAP binds specifically to IL-17A and inhibits the interaction of the cytokine with its receptor, IL-17RA. ABSTRACT |
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69 77 cytokine protein_type HAP binds specifically to IL-17A and inhibits the interaction of the cytokine with its receptor, IL-17RA. ABSTRACT |
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87 95 receptor protein_type HAP binds specifically to IL-17A and inhibits the interaction of the cytokine with its receptor, IL-17RA. ABSTRACT |
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97 104 IL-17RA protein HAP binds specifically to IL-17A and inhibits the interaction of the cytokine with its receptor, IL-17RA. ABSTRACT |
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18 23 human species Tested in primary human cells, HAP blocked the production of multiple inflammatory cytokines. ABSTRACT |
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31 34 HAP chemical Tested in primary human cells, HAP blocked the production of multiple inflammatory cytokines. ABSTRACT |
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83 92 cytokines protein_type Tested in primary human cells, HAP blocked the production of multiple inflammatory cytokines. ABSTRACT |
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0 25 Crystal structure studies experimental_method Crystal structure studies revealed that two HAP molecules bind to one IL-17A dimer symmetrically. ABSTRACT |
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44 47 HAP chemical Crystal structure studies revealed that two HAP molecules bind to one IL-17A dimer symmetrically. ABSTRACT |
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70 76 IL-17A protein Crystal structure studies revealed that two HAP molecules bind to one IL-17A dimer symmetrically. ABSTRACT |
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77 82 dimer oligomeric_state Crystal structure studies revealed that two HAP molecules bind to one IL-17A dimer symmetrically. ABSTRACT |
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27 30 HAP chemical The N-terminal portions of HAP form a β-strand that inserts between two IL-17A monomers while the C-terminal section forms an α helix that directly blocks IL-17RA from binding to the same region of IL-17A. ABSTRACT |
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38 46 β-strand structure_element The N-terminal portions of HAP form a β-strand that inserts between two IL-17A monomers while the C-terminal section forms an α helix that directly blocks IL-17RA from binding to the same region of IL-17A. ABSTRACT |
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72 78 IL-17A protein The N-terminal portions of HAP form a β-strand that inserts between two IL-17A monomers while the C-terminal section forms an α helix that directly blocks IL-17RA from binding to the same region of IL-17A. ABSTRACT |
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79 87 monomers oligomeric_state The N-terminal portions of HAP form a β-strand that inserts between two IL-17A monomers while the C-terminal section forms an α helix that directly blocks IL-17RA from binding to the same region of IL-17A. ABSTRACT |
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126 133 α helix structure_element The N-terminal portions of HAP form a β-strand that inserts between two IL-17A monomers while the C-terminal section forms an α helix that directly blocks IL-17RA from binding to the same region of IL-17A. ABSTRACT |
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155 162 IL-17RA protein The N-terminal portions of HAP form a β-strand that inserts between two IL-17A monomers while the C-terminal section forms an α helix that directly blocks IL-17RA from binding to the same region of IL-17A. ABSTRACT |
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198 204 IL-17A protein The N-terminal portions of HAP form a β-strand that inserts between two IL-17A monomers while the C-terminal section forms an α helix that directly blocks IL-17RA from binding to the same region of IL-17A. ABSTRACT |
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14 29 IL-17 cytokines protein_type The family of IL-17 cytokines and receptors consists of six polypeptides, IL-17A-F, and five receptors, IL-17RA-E. IL-17A is secreted from activated Th17 cells, and several innate immune T cell types including macrophages, neutrophils, natural killer cells, and dendritic cells. INTRO |
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74 82 IL-17A-F protein The family of IL-17 cytokines and receptors consists of six polypeptides, IL-17A-F, and five receptors, IL-17RA-E. IL-17A is secreted from activated Th17 cells, and several innate immune T cell types including macrophages, neutrophils, natural killer cells, and dendritic cells. INTRO |
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104 113 IL-17RA-E protein The family of IL-17 cytokines and receptors consists of six polypeptides, IL-17A-F, and five receptors, IL-17RA-E. IL-17A is secreted from activated Th17 cells, and several innate immune T cell types including macrophages, neutrophils, natural killer cells, and dendritic cells. INTRO |
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115 121 IL-17A protein The family of IL-17 cytokines and receptors consists of six polypeptides, IL-17A-F, and five receptors, IL-17RA-E. IL-17A is secreted from activated Th17 cells, and several innate immune T cell types including macrophages, neutrophils, natural killer cells, and dendritic cells. INTRO |
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0 6 IL-17A protein IL-17A signals through a specific cell surface receptor complex which consists of IL-17RA and IL-17RC. INTRO |
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47 55 receptor protein_type IL-17A signals through a specific cell surface receptor complex which consists of IL-17RA and IL-17RC. INTRO |
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82 89 IL-17RA protein IL-17A signals through a specific cell surface receptor complex which consists of IL-17RA and IL-17RC. INTRO |
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94 101 IL-17RC protein IL-17A signals through a specific cell surface receptor complex which consists of IL-17RA and IL-17RC. INTRO |
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0 6 IL-17A protein IL-17A’s downstream signaling leads to increased production of inflammatory cytokines such as IL-6, IL-8, CCL-20 and CXCL1 by various mechanisms including stimulation of transcription and stabilization of mRNA. INTRO |
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76 85 cytokines protein_type IL-17A’s downstream signaling leads to increased production of inflammatory cytokines such as IL-6, IL-8, CCL-20 and CXCL1 by various mechanisms including stimulation of transcription and stabilization of mRNA. INTRO |
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94 98 IL-6 protein_type IL-17A’s downstream signaling leads to increased production of inflammatory cytokines such as IL-6, IL-8, CCL-20 and CXCL1 by various mechanisms including stimulation of transcription and stabilization of mRNA. INTRO |
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100 104 IL-8 protein_type IL-17A’s downstream signaling leads to increased production of inflammatory cytokines such as IL-6, IL-8, CCL-20 and CXCL1 by various mechanisms including stimulation of transcription and stabilization of mRNA. INTRO |
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106 112 CCL-20 protein_type IL-17A’s downstream signaling leads to increased production of inflammatory cytokines such as IL-6, IL-8, CCL-20 and CXCL1 by various mechanisms including stimulation of transcription and stabilization of mRNA. INTRO |
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117 122 CXCL1 protein_type IL-17A’s downstream signaling leads to increased production of inflammatory cytokines such as IL-6, IL-8, CCL-20 and CXCL1 by various mechanisms including stimulation of transcription and stabilization of mRNA. INTRO |
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205 209 mRNA chemical IL-17A’s downstream signaling leads to increased production of inflammatory cytokines such as IL-6, IL-8, CCL-20 and CXCL1 by various mechanisms including stimulation of transcription and stabilization of mRNA. INTRO |
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58 65 IL-17RA protein Although various cell types have been reported to express IL-17RA, the highest responses to IL-17A come from epithelial cells, endothelial cells, keratinocytes and fibroblasts. INTRO |
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92 98 IL-17A protein Although various cell types have been reported to express IL-17RA, the highest responses to IL-17A come from epithelial cells, endothelial cells, keratinocytes and fibroblasts. INTRO |
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0 6 IL-17A protein IL-17A and its signaling is important in host defense against certain fungal and bacterial infections as demonstrated by patients with autoantibodies against IL-17A and IL-17F, or with inborn errors of IL-17 immunity. INTRO |
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158 164 IL-17A protein IL-17A and its signaling is important in host defense against certain fungal and bacterial infections as demonstrated by patients with autoantibodies against IL-17A and IL-17F, or with inborn errors of IL-17 immunity. INTRO |
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169 175 IL-17F protein IL-17A and its signaling is important in host defense against certain fungal and bacterial infections as demonstrated by patients with autoantibodies against IL-17A and IL-17F, or with inborn errors of IL-17 immunity. INTRO |
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202 207 IL-17 protein_type IL-17A and its signaling is important in host defense against certain fungal and bacterial infections as demonstrated by patients with autoantibodies against IL-17A and IL-17F, or with inborn errors of IL-17 immunity. INTRO |
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39 45 IL-17A protein In addition to its physiological role, IL-17A is a key pathogenic factor in inflammatory and autoimmune diseases. INTRO |
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61 71 antibodies protein_type In phase II and III clinical trials, neutralizing monoclonal antibodies against IL-17A (secukinumab and ixekizumab) or its receptor IL-17RA (brodalumab) are highly efficacious in treating moderate to severe plaque psoriasis and psoriatic arthritis. INTRO |
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80 86 IL-17A protein In phase II and III clinical trials, neutralizing monoclonal antibodies against IL-17A (secukinumab and ixekizumab) or its receptor IL-17RA (brodalumab) are highly efficacious in treating moderate to severe plaque psoriasis and psoriatic arthritis. INTRO |
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88 99 secukinumab chemical In phase II and III clinical trials, neutralizing monoclonal antibodies against IL-17A (secukinumab and ixekizumab) or its receptor IL-17RA (brodalumab) are highly efficacious in treating moderate to severe plaque psoriasis and psoriatic arthritis. INTRO |
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104 114 ixekizumab chemical In phase II and III clinical trials, neutralizing monoclonal antibodies against IL-17A (secukinumab and ixekizumab) or its receptor IL-17RA (brodalumab) are highly efficacious in treating moderate to severe plaque psoriasis and psoriatic arthritis. INTRO |
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123 131 receptor protein_type In phase II and III clinical trials, neutralizing monoclonal antibodies against IL-17A (secukinumab and ixekizumab) or its receptor IL-17RA (brodalumab) are highly efficacious in treating moderate to severe plaque psoriasis and psoriatic arthritis. INTRO |
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132 139 IL-17RA protein In phase II and III clinical trials, neutralizing monoclonal antibodies against IL-17A (secukinumab and ixekizumab) or its receptor IL-17RA (brodalumab) are highly efficacious in treating moderate to severe plaque psoriasis and psoriatic arthritis. INTRO |
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141 151 brodalumab chemical In phase II and III clinical trials, neutralizing monoclonal antibodies against IL-17A (secukinumab and ixekizumab) or its receptor IL-17RA (brodalumab) are highly efficacious in treating moderate to severe plaque psoriasis and psoriatic arthritis. INTRO |
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0 11 Secukinumab chemical Secukinumab has been approved recently as a new psoriasis drug by the US Food and Drug Administration (Cosentyx™). INTRO |
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103 112 Cosentyx™ chemical Secukinumab has been approved recently as a new psoriasis drug by the US Food and Drug Administration (Cosentyx™). INTRO |
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50 56 IL-17A protein In addition to psoriasis and psoriatic arthritis, IL-17A blockade has also shown preclinical and clinical efficacies in ankylosing spondylitis and rheumatoid arthritis. INTRO |
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6 21 IL-17 cytokines protein_type Among IL-17 cytokines, IL-17A and IL-17F share the highest homology. INTRO |
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23 29 IL-17A protein Among IL-17 cytokines, IL-17A and IL-17F share the highest homology. INTRO |
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34 40 IL-17F protein Among IL-17 cytokines, IL-17A and IL-17F share the highest homology. INTRO |
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24 32 covalent protein_state These polypeptides form covalent homodimers, and IL-17A and IL-17F also form an IL-17A/IL-17F hetereodimer. INTRO |
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33 43 homodimers oligomeric_state These polypeptides form covalent homodimers, and IL-17A and IL-17F also form an IL-17A/IL-17F hetereodimer. INTRO |
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49 55 IL-17A protein These polypeptides form covalent homodimers, and IL-17A and IL-17F also form an IL-17A/IL-17F hetereodimer. INTRO |
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60 66 IL-17F protein These polypeptides form covalent homodimers, and IL-17A and IL-17F also form an IL-17A/IL-17F hetereodimer. INTRO |
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80 93 IL-17A/IL-17F complex_assembly These polypeptides form covalent homodimers, and IL-17A and IL-17F also form an IL-17A/IL-17F hetereodimer. INTRO |
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94 106 hetereodimer oligomeric_state These polypeptides form covalent homodimers, and IL-17A and IL-17F also form an IL-17A/IL-17F hetereodimer. INTRO |
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0 10 Structures evidence Structures are known for apo IL-17F and its complex with IL-17RA, for apo IL-17A, its complex with an antibody Fab, and its complex with IL-17RA. INTRO |
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25 28 apo protein_state Structures are known for apo IL-17F and its complex with IL-17RA, for apo IL-17A, its complex with an antibody Fab, and its complex with IL-17RA. INTRO |
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29 35 IL-17F protein Structures are known for apo IL-17F and its complex with IL-17RA, for apo IL-17A, its complex with an antibody Fab, and its complex with IL-17RA. INTRO |
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44 56 complex with protein_state Structures are known for apo IL-17F and its complex with IL-17RA, for apo IL-17A, its complex with an antibody Fab, and its complex with IL-17RA. INTRO |
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57 64 IL-17RA protein Structures are known for apo IL-17F and its complex with IL-17RA, for apo IL-17A, its complex with an antibody Fab, and its complex with IL-17RA. INTRO |
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70 73 apo protein_state Structures are known for apo IL-17F and its complex with IL-17RA, for apo IL-17A, its complex with an antibody Fab, and its complex with IL-17RA. INTRO |
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74 80 IL-17A protein Structures are known for apo IL-17F and its complex with IL-17RA, for apo IL-17A, its complex with an antibody Fab, and its complex with IL-17RA. INTRO |
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86 98 complex with protein_state Structures are known for apo IL-17F and its complex with IL-17RA, for apo IL-17A, its complex with an antibody Fab, and its complex with IL-17RA. INTRO |
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102 110 antibody protein_type Structures are known for apo IL-17F and its complex with IL-17RA, for apo IL-17A, its complex with an antibody Fab, and its complex with IL-17RA. INTRO |
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111 114 Fab structure_element Structures are known for apo IL-17F and its complex with IL-17RA, for apo IL-17A, its complex with an antibody Fab, and its complex with IL-17RA. INTRO |
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124 136 complex with protein_state Structures are known for apo IL-17F and its complex with IL-17RA, for apo IL-17A, its complex with an antibody Fab, and its complex with IL-17RA. INTRO |
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137 144 IL-17RA protein Structures are known for apo IL-17F and its complex with IL-17RA, for apo IL-17A, its complex with an antibody Fab, and its complex with IL-17RA. INTRO |
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9 19 structures evidence In these structures, both IL-17A and IL-17F adopt a cysteine-knot fold with two intramolecular disulfides and two interchain disulfide bonds that covalently link two monomers. INTRO |
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26 32 IL-17A protein In these structures, both IL-17A and IL-17F adopt a cysteine-knot fold with two intramolecular disulfides and two interchain disulfide bonds that covalently link two monomers. INTRO |
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37 43 IL-17F protein In these structures, both IL-17A and IL-17F adopt a cysteine-knot fold with two intramolecular disulfides and two interchain disulfide bonds that covalently link two monomers. INTRO |
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52 65 cysteine-knot structure_element In these structures, both IL-17A and IL-17F adopt a cysteine-knot fold with two intramolecular disulfides and two interchain disulfide bonds that covalently link two monomers. INTRO |
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95 105 disulfides ptm In these structures, both IL-17A and IL-17F adopt a cysteine-knot fold with two intramolecular disulfides and two interchain disulfide bonds that covalently link two monomers. INTRO |
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125 140 disulfide bonds ptm In these structures, both IL-17A and IL-17F adopt a cysteine-knot fold with two intramolecular disulfides and two interchain disulfide bonds that covalently link two monomers. INTRO |
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166 174 monomers oligomeric_state In these structures, both IL-17A and IL-17F adopt a cysteine-knot fold with two intramolecular disulfides and two interchain disulfide bonds that covalently link two monomers. INTRO |
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116 122 IL-17A protein There has been active research in identifying orally available chemical entities that would functionally antagonize IL-17A-mediated signaling. INTRO |
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141 166 IL-17A/IL-17RA interfaces site Developing small molecules targeting protein-protein interactions is difficult with particular challenges associated with the large, shallow IL-17A/IL-17RA interfaces. INTRO |
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6 13 IL-17RA protein Since IL-17RA is a shared receptor for at least IL-17A, IL-17F, IL-17A/IL-17F and IL-17E, we chose to seek IL-17A-specific inhibitors that may have more defined pharmacological responses than IL-17RA inhibitors. INTRO |
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26 34 receptor protein_type Since IL-17RA is a shared receptor for at least IL-17A, IL-17F, IL-17A/IL-17F and IL-17E, we chose to seek IL-17A-specific inhibitors that may have more defined pharmacological responses than IL-17RA inhibitors. INTRO |
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48 54 IL-17A protein Since IL-17RA is a shared receptor for at least IL-17A, IL-17F, IL-17A/IL-17F and IL-17E, we chose to seek IL-17A-specific inhibitors that may have more defined pharmacological responses than IL-17RA inhibitors. INTRO |
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56 62 IL-17F protein Since IL-17RA is a shared receptor for at least IL-17A, IL-17F, IL-17A/IL-17F and IL-17E, we chose to seek IL-17A-specific inhibitors that may have more defined pharmacological responses than IL-17RA inhibitors. INTRO |
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64 77 IL-17A/IL-17F complex_assembly Since IL-17RA is a shared receptor for at least IL-17A, IL-17F, IL-17A/IL-17F and IL-17E, we chose to seek IL-17A-specific inhibitors that may have more defined pharmacological responses than IL-17RA inhibitors. INTRO |
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82 88 IL-17E protein Since IL-17RA is a shared receptor for at least IL-17A, IL-17F, IL-17A/IL-17F and IL-17E, we chose to seek IL-17A-specific inhibitors that may have more defined pharmacological responses than IL-17RA inhibitors. INTRO |
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107 113 IL-17A protein Since IL-17RA is a shared receptor for at least IL-17A, IL-17F, IL-17A/IL-17F and IL-17E, we chose to seek IL-17A-specific inhibitors that may have more defined pharmacological responses than IL-17RA inhibitors. INTRO |
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192 199 IL-17RA protein Since IL-17RA is a shared receptor for at least IL-17A, IL-17F, IL-17A/IL-17F and IL-17E, we chose to seek IL-17A-specific inhibitors that may have more defined pharmacological responses than IL-17RA inhibitors. INTRO |
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39 78 high affinity IL-17A peptide antagonist chemical Our efforts resulted in discovery of a high affinity IL-17A peptide antagonist (HAP), which we attempted to increase the functional production and pharmacokinetics after fusing HAP to antibodies for evaluation as a bispecific therapeutic in animal studies. INTRO |
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80 83 HAP chemical Our efforts resulted in discovery of a high affinity IL-17A peptide antagonist (HAP), which we attempted to increase the functional production and pharmacokinetics after fusing HAP to antibodies for evaluation as a bispecific therapeutic in animal studies. INTRO |
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170 176 fusing experimental_method Our efforts resulted in discovery of a high affinity IL-17A peptide antagonist (HAP), which we attempted to increase the functional production and pharmacokinetics after fusing HAP to antibodies for evaluation as a bispecific therapeutic in animal studies. INTRO |
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177 180 HAP chemical Our efforts resulted in discovery of a high affinity IL-17A peptide antagonist (HAP), which we attempted to increase the functional production and pharmacokinetics after fusing HAP to antibodies for evaluation as a bispecific therapeutic in animal studies. INTRO |
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184 194 antibodies protein_type Our efforts resulted in discovery of a high affinity IL-17A peptide antagonist (HAP), which we attempted to increase the functional production and pharmacokinetics after fusing HAP to antibodies for evaluation as a bispecific therapeutic in animal studies. INTRO |
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63 71 uncapped protein_state Unfortunately, this past work revealed stability issues of the uncapped HAP in cell culture Here, we provide the details of the discovery and optimization that led to HAP and report the complex structure of IL-17A with HAP, which provides structure based rationalization of peptide optimization and structure activity relationship (SAR). INTRO |
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72 75 HAP chemical Unfortunately, this past work revealed stability issues of the uncapped HAP in cell culture Here, we provide the details of the discovery and optimization that led to HAP and report the complex structure of IL-17A with HAP, which provides structure based rationalization of peptide optimization and structure activity relationship (SAR). INTRO |
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167 170 HAP chemical Unfortunately, this past work revealed stability issues of the uncapped HAP in cell culture Here, we provide the details of the discovery and optimization that led to HAP and report the complex structure of IL-17A with HAP, which provides structure based rationalization of peptide optimization and structure activity relationship (SAR). INTRO |
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186 203 complex structure evidence Unfortunately, this past work revealed stability issues of the uncapped HAP in cell culture Here, we provide the details of the discovery and optimization that led to HAP and report the complex structure of IL-17A with HAP, which provides structure based rationalization of peptide optimization and structure activity relationship (SAR). INTRO |
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207 213 IL-17A protein Unfortunately, this past work revealed stability issues of the uncapped HAP in cell culture Here, we provide the details of the discovery and optimization that led to HAP and report the complex structure of IL-17A with HAP, which provides structure based rationalization of peptide optimization and structure activity relationship (SAR). INTRO |
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219 222 HAP chemical Unfortunately, this past work revealed stability issues of the uncapped HAP in cell culture Here, we provide the details of the discovery and optimization that led to HAP and report the complex structure of IL-17A with HAP, which provides structure based rationalization of peptide optimization and structure activity relationship (SAR). INTRO |
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274 294 peptide optimization experimental_method Unfortunately, this past work revealed stability issues of the uncapped HAP in cell culture Here, we provide the details of the discovery and optimization that led to HAP and report the complex structure of IL-17A with HAP, which provides structure based rationalization of peptide optimization and structure activity relationship (SAR). INTRO |
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299 330 structure activity relationship experimental_method Unfortunately, this past work revealed stability issues of the uncapped HAP in cell culture Here, we provide the details of the discovery and optimization that led to HAP and report the complex structure of IL-17A with HAP, which provides structure based rationalization of peptide optimization and structure activity relationship (SAR). INTRO |
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332 335 SAR experimental_method Unfortunately, this past work revealed stability issues of the uncapped HAP in cell culture Here, we provide the details of the discovery and optimization that led to HAP and report the complex structure of IL-17A with HAP, which provides structure based rationalization of peptide optimization and structure activity relationship (SAR). INTRO |
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18 24 IL-17A protein Identification of IL-17A peptide inhibitors RESULTS |
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33 38 human species Peptides specifically binding to human IL-17A were identified from phage panning using cyclic and linear peptide libraries (Supplementary Figure S1). RESULTS |
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39 45 IL-17A protein Peptides specifically binding to human IL-17A were identified from phage panning using cyclic and linear peptide libraries (Supplementary Figure S1). RESULTS |
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67 80 phage panning experimental_method Peptides specifically binding to human IL-17A were identified from phage panning using cyclic and linear peptide libraries (Supplementary Figure S1). RESULTS |
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87 122 cyclic and linear peptide libraries experimental_method Peptides specifically binding to human IL-17A were identified from phage panning using cyclic and linear peptide libraries (Supplementary Figure S1). RESULTS |
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0 20 Positive phage pools experimental_method Positive phage pools were then sub-cloned into a maltose-binding protein (MBP) fusion system. RESULTS |
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31 41 sub-cloned experimental_method Positive phage pools were then sub-cloned into a maltose-binding protein (MBP) fusion system. RESULTS |
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49 92 maltose-binding protein (MBP) fusion system experimental_method Positive phage pools were then sub-cloned into a maltose-binding protein (MBP) fusion system. RESULTS |
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104 137 enzyme-linked immunosorbent assay experimental_method Single clones were isolated and sub-cultured in growth medium, and culture supernatants were used in an enzyme-linked immunosorbent assay (ELISA) to identify specific IL-17A-binding clones. RESULTS |
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139 144 ELISA experimental_method Single clones were isolated and sub-cultured in growth medium, and culture supernatants were used in an enzyme-linked immunosorbent assay (ELISA) to identify specific IL-17A-binding clones. RESULTS |
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167 173 IL-17A protein Single clones were isolated and sub-cultured in growth medium, and culture supernatants were used in an enzyme-linked immunosorbent assay (ELISA) to identify specific IL-17A-binding clones. RESULTS |
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71 83 biotinylated protein_state The positive binding supernatants were tested for the ability to block biotinylated IL-17A signaling through IL-17RA in an IL-17A/IL-17RA competition ELISA assay where unlabeled IL-17A was used as positive control to inhibit biotinylated IL-17A binding. RESULTS |
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84 90 IL-17A protein The positive binding supernatants were tested for the ability to block biotinylated IL-17A signaling through IL-17RA in an IL-17A/IL-17RA competition ELISA assay where unlabeled IL-17A was used as positive control to inhibit biotinylated IL-17A binding. RESULTS |
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109 116 IL-17RA protein The positive binding supernatants were tested for the ability to block biotinylated IL-17A signaling through IL-17RA in an IL-17A/IL-17RA competition ELISA assay where unlabeled IL-17A was used as positive control to inhibit biotinylated IL-17A binding. RESULTS |
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123 137 IL-17A/IL-17RA complex_assembly The positive binding supernatants were tested for the ability to block biotinylated IL-17A signaling through IL-17RA in an IL-17A/IL-17RA competition ELISA assay where unlabeled IL-17A was used as positive control to inhibit biotinylated IL-17A binding. RESULTS |
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138 161 competition ELISA assay experimental_method The positive binding supernatants were tested for the ability to block biotinylated IL-17A signaling through IL-17RA in an IL-17A/IL-17RA competition ELISA assay where unlabeled IL-17A was used as positive control to inhibit biotinylated IL-17A binding. RESULTS |
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178 184 IL-17A protein The positive binding supernatants were tested for the ability to block biotinylated IL-17A signaling through IL-17RA in an IL-17A/IL-17RA competition ELISA assay where unlabeled IL-17A was used as positive control to inhibit biotinylated IL-17A binding. RESULTS |
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225 237 biotinylated protein_state The positive binding supernatants were tested for the ability to block biotinylated IL-17A signaling through IL-17RA in an IL-17A/IL-17RA competition ELISA assay where unlabeled IL-17A was used as positive control to inhibit biotinylated IL-17A binding. RESULTS |
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238 244 IL-17A protein The positive binding supernatants were tested for the ability to block biotinylated IL-17A signaling through IL-17RA in an IL-17A/IL-17RA competition ELISA assay where unlabeled IL-17A was used as positive control to inhibit biotinylated IL-17A binding. RESULTS |
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59 65 IL-17A protein Approximately 10% of the clones that specifically bound to IL-17A also prevented the cytokine from binding to IL-17RA. RESULTS |
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85 93 cytokine protein_type Approximately 10% of the clones that specifically bound to IL-17A also prevented the cytokine from binding to IL-17RA. RESULTS |
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110 117 IL-17RA protein Approximately 10% of the clones that specifically bound to IL-17A also prevented the cytokine from binding to IL-17RA. RESULTS |
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26 38 phage clones experimental_method Sequences identified from phage clones were chemically synthesized (Supplementary Table 1) and tested for inhibition of IL-17A binding to IL-17RA (Table 1). RESULTS |
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44 66 chemically synthesized experimental_method Sequences identified from phage clones were chemically synthesized (Supplementary Table 1) and tested for inhibition of IL-17A binding to IL-17RA (Table 1). RESULTS |
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120 126 IL-17A protein Sequences identified from phage clones were chemically synthesized (Supplementary Table 1) and tested for inhibition of IL-17A binding to IL-17RA (Table 1). RESULTS |
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138 145 IL-17RA protein Sequences identified from phage clones were chemically synthesized (Supplementary Table 1) and tested for inhibition of IL-17A binding to IL-17RA (Table 1). RESULTS |
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16 25 peptide 1 chemical A 15-mer linear peptide 1 was shown to block IL-17A/IL-17RA binding with an IC50 of 80 nM in the competition ELISA assay (Table 1). RESULTS |
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45 59 IL-17A/IL-17RA complex_assembly A 15-mer linear peptide 1 was shown to block IL-17A/IL-17RA binding with an IC50 of 80 nM in the competition ELISA assay (Table 1). RESULTS |
|
76 80 IC50 evidence A 15-mer linear peptide 1 was shown to block IL-17A/IL-17RA binding with an IC50 of 80 nM in the competition ELISA assay (Table 1). RESULTS |
|
97 120 competition ELISA assay experimental_method A 15-mer linear peptide 1 was shown to block IL-17A/IL-17RA binding with an IC50 of 80 nM in the competition ELISA assay (Table 1). RESULTS |
|
34 61 cell-based functional assay experimental_method This peptide was then tested in a cell-based functional assay wherein production of GRO-α in BJ human fibroblast cells was measured as a function of IL-17A stimulation using 1 ng/ml IL-17A. RESULTS |
|
84 89 GRO-α protein This peptide was then tested in a cell-based functional assay wherein production of GRO-α in BJ human fibroblast cells was measured as a function of IL-17A stimulation using 1 ng/ml IL-17A. RESULTS |
|
96 101 human species This peptide was then tested in a cell-based functional assay wherein production of GRO-α in BJ human fibroblast cells was measured as a function of IL-17A stimulation using 1 ng/ml IL-17A. RESULTS |
|
149 155 IL-17A protein This peptide was then tested in a cell-based functional assay wherein production of GRO-α in BJ human fibroblast cells was measured as a function of IL-17A stimulation using 1 ng/ml IL-17A. RESULTS |
|
182 188 IL-17A protein This peptide was then tested in a cell-based functional assay wherein production of GRO-α in BJ human fibroblast cells was measured as a function of IL-17A stimulation using 1 ng/ml IL-17A. RESULTS |
|
0 9 Peptide 1 chemical Peptide 1 was found to be active in this functional assay with an IC50 of 370 nM. RESULTS |
|
41 57 functional assay experimental_method Peptide 1 was found to be active in this functional assay with an IC50 of 370 nM. RESULTS |
|
66 70 IC50 evidence Peptide 1 was found to be active in this functional assay with an IC50 of 370 nM. RESULTS |
|
16 22 IL-17A protein Optimization of IL-17A peptide inhibitors RESULTS |
|
2 5 SAR experimental_method A SAR campaign was undertaken to improve the potency of peptide 1. RESULTS |
|
56 65 peptide 1 chemical A SAR campaign was undertaken to improve the potency of peptide 1. RESULTS |
|
3 15 alanine scan experimental_method An alanine scan of peptide 2, an analogue of 1 with a lysine to arginine substitution at position 14, was initiated. RESULTS |
|
19 28 peptide 2 chemical An alanine scan of peptide 2, an analogue of 1 with a lysine to arginine substitution at position 14, was initiated. RESULTS |
|
45 46 1 chemical An alanine scan of peptide 2, an analogue of 1 with a lysine to arginine substitution at position 14, was initiated. RESULTS |
|
54 60 lysine residue_name An alanine scan of peptide 2, an analogue of 1 with a lysine to arginine substitution at position 14, was initiated. RESULTS |
|
64 72 arginine residue_name An alanine scan of peptide 2, an analogue of 1 with a lysine to arginine substitution at position 14, was initiated. RESULTS |
|
73 85 substitution experimental_method An alanine scan of peptide 2, an analogue of 1 with a lysine to arginine substitution at position 14, was initiated. RESULTS |
|
98 100 14 residue_number An alanine scan of peptide 2, an analogue of 1 with a lysine to arginine substitution at position 14, was initiated. RESULTS |
|
5 12 alanine residue_name When alanine was already present (positions 7 and 15), substitution was made with lysine (Table 1, peptides 3–17). RESULTS |
|
44 45 7 residue_number When alanine was already present (positions 7 and 15), substitution was made with lysine (Table 1, peptides 3–17). RESULTS |
|
50 52 15 residue_number When alanine was already present (positions 7 and 15), substitution was made with lysine (Table 1, peptides 3–17). RESULTS |
|
55 67 substitution experimental_method When alanine was already present (positions 7 and 15), substitution was made with lysine (Table 1, peptides 3–17). RESULTS |
|
82 88 lysine residue_name When alanine was already present (positions 7 and 15), substitution was made with lysine (Table 1, peptides 3–17). RESULTS |
|
99 112 peptides 3–17 chemical When alanine was already present (positions 7 and 15), substitution was made with lysine (Table 1, peptides 3–17). RESULTS |
|
10 11 1 residue_number Positions 1, 2, 4, 5, 7, 14 and 15 were shown to be amenable to substitution without significant loss (less than 3-fold) of binding affinity as measured by the IL-17A/IL-17RA competition ELISA. RESULTS |
|
13 14 2 residue_number Positions 1, 2, 4, 5, 7, 14 and 15 were shown to be amenable to substitution without significant loss (less than 3-fold) of binding affinity as measured by the IL-17A/IL-17RA competition ELISA. RESULTS |
|
16 17 4 residue_number Positions 1, 2, 4, 5, 7, 14 and 15 were shown to be amenable to substitution without significant loss (less than 3-fold) of binding affinity as measured by the IL-17A/IL-17RA competition ELISA. RESULTS |
|
19 20 5 residue_number Positions 1, 2, 4, 5, 7, 14 and 15 were shown to be amenable to substitution without significant loss (less than 3-fold) of binding affinity as measured by the IL-17A/IL-17RA competition ELISA. RESULTS |
|
22 23 7 residue_number Positions 1, 2, 4, 5, 7, 14 and 15 were shown to be amenable to substitution without significant loss (less than 3-fold) of binding affinity as measured by the IL-17A/IL-17RA competition ELISA. RESULTS |
|
25 27 14 residue_number Positions 1, 2, 4, 5, 7, 14 and 15 were shown to be amenable to substitution without significant loss (less than 3-fold) of binding affinity as measured by the IL-17A/IL-17RA competition ELISA. RESULTS |
|
32 34 15 residue_number Positions 1, 2, 4, 5, 7, 14 and 15 were shown to be amenable to substitution without significant loss (less than 3-fold) of binding affinity as measured by the IL-17A/IL-17RA competition ELISA. RESULTS |
|
124 140 binding affinity evidence Positions 1, 2, 4, 5, 7, 14 and 15 were shown to be amenable to substitution without significant loss (less than 3-fold) of binding affinity as measured by the IL-17A/IL-17RA competition ELISA. RESULTS |
|
160 174 IL-17A/IL-17RA complex_assembly Positions 1, 2, 4, 5, 7, 14 and 15 were shown to be amenable to substitution without significant loss (less than 3-fold) of binding affinity as measured by the IL-17A/IL-17RA competition ELISA. RESULTS |
|
175 192 competition ELISA experimental_method Positions 1, 2, 4, 5, 7, 14 and 15 were shown to be amenable to substitution without significant loss (less than 3-fold) of binding affinity as measured by the IL-17A/IL-17RA competition ELISA. RESULTS |
|
27 28 5 residue_number In particular, at position 5 (13), substitution of methionine with alanine resulted in a seven fold improvement in potency (80 nM versus 11 nM respectively). RESULTS |
|
30 32 13 chemical In particular, at position 5 (13), substitution of methionine with alanine resulted in a seven fold improvement in potency (80 nM versus 11 nM respectively). RESULTS |
|
35 47 substitution experimental_method In particular, at position 5 (13), substitution of methionine with alanine resulted in a seven fold improvement in potency (80 nM versus 11 nM respectively). RESULTS |
|
51 61 methionine residue_name In particular, at position 5 (13), substitution of methionine with alanine resulted in a seven fold improvement in potency (80 nM versus 11 nM respectively). RESULTS |
|
67 74 alanine residue_name In particular, at position 5 (13), substitution of methionine with alanine resulted in a seven fold improvement in potency (80 nM versus 11 nM respectively). RESULTS |
|
44 56 substitution experimental_method In order to rapidly evaluate the effects of substitution of natural amino acids at tolerant positions identified by the alanine scan, the lead sequence was subjected to site-specific saturation mutagenesis using MBP. RESULTS |
|
120 132 alanine scan experimental_method In order to rapidly evaluate the effects of substitution of natural amino acids at tolerant positions identified by the alanine scan, the lead sequence was subjected to site-specific saturation mutagenesis using MBP. RESULTS |
|
169 205 site-specific saturation mutagenesis experimental_method In order to rapidly evaluate the effects of substitution of natural amino acids at tolerant positions identified by the alanine scan, the lead sequence was subjected to site-specific saturation mutagenesis using MBP. RESULTS |
|
212 215 MBP experimental_method In order to rapidly evaluate the effects of substitution of natural amino acids at tolerant positions identified by the alanine scan, the lead sequence was subjected to site-specific saturation mutagenesis using MBP. RESULTS |
|
46 58 alanine scan experimental_method Each of the seven positions identified by the alanine scan was individually modified while keeping the rest of the sequence constant. RESULTS |
|
27 28 2 residue_number Modifications at positions 2 and 14 were shown to display improvement in binding affinity (data not shown). RESULTS |
|
33 35 14 residue_number Modifications at positions 2 and 14 were shown to display improvement in binding affinity (data not shown). RESULTS |
|
73 89 binding affinity evidence Modifications at positions 2 and 14 were shown to display improvement in binding affinity (data not shown). RESULTS |
|
25 40 point mutations experimental_method Peptides with beneficial point mutations at positions 2, 5, and 14 were synthesized and evaluated in the competition ELISA (Table 1). RESULTS |
|
54 55 2 residue_number Peptides with beneficial point mutations at positions 2, 5, and 14 were synthesized and evaluated in the competition ELISA (Table 1). RESULTS |
|
57 58 5 residue_number Peptides with beneficial point mutations at positions 2, 5, and 14 were synthesized and evaluated in the competition ELISA (Table 1). RESULTS |
|
64 66 14 residue_number Peptides with beneficial point mutations at positions 2, 5, and 14 were synthesized and evaluated in the competition ELISA (Table 1). RESULTS |
|
72 83 synthesized experimental_method Peptides with beneficial point mutations at positions 2, 5, and 14 were synthesized and evaluated in the competition ELISA (Table 1). RESULTS |
|
105 122 competition ELISA experimental_method Peptides with beneficial point mutations at positions 2, 5, and 14 were synthesized and evaluated in the competition ELISA (Table 1). RESULTS |
|
20 23 V2H mutant Two of the changes, V2H (18) or V2T (21) displayed improved binding in the competition ELISA. RESULTS |
|
25 27 18 chemical Two of the changes, V2H (18) or V2T (21) displayed improved binding in the competition ELISA. RESULTS |
|
32 35 V2T mutant Two of the changes, V2H (18) or V2T (21) displayed improved binding in the competition ELISA. RESULTS |
|
37 39 21 chemical Two of the changes, V2H (18) or V2T (21) displayed improved binding in the competition ELISA. RESULTS |
|
75 92 competition ELISA experimental_method Two of the changes, V2H (18) or V2T (21) displayed improved binding in the competition ELISA. RESULTS |
|
10 21 replacement experimental_method Since the replacement of methionine at position 5 with alanine was beneficial, the additional hydrophobic amino acids isoleucine (24), leucine (25) and valine (26) were evaluated and an additional two-three fold improvement in binding was observed for the valine and isoleucine replacements in comparison with alanine. RESULTS |
|
25 35 methionine residue_name Since the replacement of methionine at position 5 with alanine was beneficial, the additional hydrophobic amino acids isoleucine (24), leucine (25) and valine (26) were evaluated and an additional two-three fold improvement in binding was observed for the valine and isoleucine replacements in comparison with alanine. RESULTS |
|
48 49 5 residue_number Since the replacement of methionine at position 5 with alanine was beneficial, the additional hydrophobic amino acids isoleucine (24), leucine (25) and valine (26) were evaluated and an additional two-three fold improvement in binding was observed for the valine and isoleucine replacements in comparison with alanine. RESULTS |
|
55 62 alanine residue_name Since the replacement of methionine at position 5 with alanine was beneficial, the additional hydrophobic amino acids isoleucine (24), leucine (25) and valine (26) were evaluated and an additional two-three fold improvement in binding was observed for the valine and isoleucine replacements in comparison with alanine. RESULTS |
|
118 128 isoleucine residue_name Since the replacement of methionine at position 5 with alanine was beneficial, the additional hydrophobic amino acids isoleucine (24), leucine (25) and valine (26) were evaluated and an additional two-three fold improvement in binding was observed for the valine and isoleucine replacements in comparison with alanine. RESULTS |
|
130 132 24 chemical Since the replacement of methionine at position 5 with alanine was beneficial, the additional hydrophobic amino acids isoleucine (24), leucine (25) and valine (26) were evaluated and an additional two-three fold improvement in binding was observed for the valine and isoleucine replacements in comparison with alanine. RESULTS |
|
135 142 leucine residue_name Since the replacement of methionine at position 5 with alanine was beneficial, the additional hydrophobic amino acids isoleucine (24), leucine (25) and valine (26) were evaluated and an additional two-three fold improvement in binding was observed for the valine and isoleucine replacements in comparison with alanine. RESULTS |
|
144 146 25 chemical Since the replacement of methionine at position 5 with alanine was beneficial, the additional hydrophobic amino acids isoleucine (24), leucine (25) and valine (26) were evaluated and an additional two-three fold improvement in binding was observed for the valine and isoleucine replacements in comparison with alanine. RESULTS |
|
152 158 valine residue_name Since the replacement of methionine at position 5 with alanine was beneficial, the additional hydrophobic amino acids isoleucine (24), leucine (25) and valine (26) were evaluated and an additional two-three fold improvement in binding was observed for the valine and isoleucine replacements in comparison with alanine. RESULTS |
|
160 162 26 chemical Since the replacement of methionine at position 5 with alanine was beneficial, the additional hydrophobic amino acids isoleucine (24), leucine (25) and valine (26) were evaluated and an additional two-three fold improvement in binding was observed for the valine and isoleucine replacements in comparison with alanine. RESULTS |
|
256 262 valine residue_name Since the replacement of methionine at position 5 with alanine was beneficial, the additional hydrophobic amino acids isoleucine (24), leucine (25) and valine (26) were evaluated and an additional two-three fold improvement in binding was observed for the valine and isoleucine replacements in comparison with alanine. RESULTS |
|
267 277 isoleucine residue_name Since the replacement of methionine at position 5 with alanine was beneficial, the additional hydrophobic amino acids isoleucine (24), leucine (25) and valine (26) were evaluated and an additional two-three fold improvement in binding was observed for the valine and isoleucine replacements in comparison with alanine. RESULTS |
|
278 290 replacements experimental_method Since the replacement of methionine at position 5 with alanine was beneficial, the additional hydrophobic amino acids isoleucine (24), leucine (25) and valine (26) were evaluated and an additional two-three fold improvement in binding was observed for the valine and isoleucine replacements in comparison with alanine. RESULTS |
|
310 317 alanine residue_name Since the replacement of methionine at position 5 with alanine was beneficial, the additional hydrophobic amino acids isoleucine (24), leucine (25) and valine (26) were evaluated and an additional two-three fold improvement in binding was observed for the valine and isoleucine replacements in comparison with alanine. RESULTS |
|
0 12 Introduction experimental_method Introduction of a methionine (27) or a carboxamide (28 and 29) at position 14 was shown to improve the binding affinity of the lead peptide. RESULTS |
|
18 28 methionine residue_name Introduction of a methionine (27) or a carboxamide (28 and 29) at position 14 was shown to improve the binding affinity of the lead peptide. RESULTS |
|
30 32 27 chemical Introduction of a methionine (27) or a carboxamide (28 and 29) at position 14 was shown to improve the binding affinity of the lead peptide. RESULTS |
|
39 50 carboxamide chemical Introduction of a methionine (27) or a carboxamide (28 and 29) at position 14 was shown to improve the binding affinity of the lead peptide. RESULTS |
|
52 54 28 chemical Introduction of a methionine (27) or a carboxamide (28 and 29) at position 14 was shown to improve the binding affinity of the lead peptide. RESULTS |
|
59 61 29 chemical Introduction of a methionine (27) or a carboxamide (28 and 29) at position 14 was shown to improve the binding affinity of the lead peptide. RESULTS |
|
75 77 14 residue_number Introduction of a methionine (27) or a carboxamide (28 and 29) at position 14 was shown to improve the binding affinity of the lead peptide. RESULTS |
|
103 119 binding affinity evidence Introduction of a methionine (27) or a carboxamide (28 and 29) at position 14 was shown to improve the binding affinity of the lead peptide. RESULTS |
|
60 78 binding affinities evidence In general, there was good agreement between the respective binding affinities of the synthesized peptides and their MBP fusion counterparts, except for substitution of valine at position 2 to a tryptophan (22), which resulted in a fivefold loss of affinity, for the free peptide when compared with the MBP fusion. RESULTS |
|
117 127 MBP fusion experimental_method In general, there was good agreement between the respective binding affinities of the synthesized peptides and their MBP fusion counterparts, except for substitution of valine at position 2 to a tryptophan (22), which resulted in a fivefold loss of affinity, for the free peptide when compared with the MBP fusion. RESULTS |
|
153 165 substitution experimental_method In general, there was good agreement between the respective binding affinities of the synthesized peptides and their MBP fusion counterparts, except for substitution of valine at position 2 to a tryptophan (22), which resulted in a fivefold loss of affinity, for the free peptide when compared with the MBP fusion. RESULTS |
|
169 175 valine residue_name In general, there was good agreement between the respective binding affinities of the synthesized peptides and their MBP fusion counterparts, except for substitution of valine at position 2 to a tryptophan (22), which resulted in a fivefold loss of affinity, for the free peptide when compared with the MBP fusion. RESULTS |
|
188 189 2 residue_number In general, there was good agreement between the respective binding affinities of the synthesized peptides and their MBP fusion counterparts, except for substitution of valine at position 2 to a tryptophan (22), which resulted in a fivefold loss of affinity, for the free peptide when compared with the MBP fusion. RESULTS |
|
195 205 tryptophan residue_name In general, there was good agreement between the respective binding affinities of the synthesized peptides and their MBP fusion counterparts, except for substitution of valine at position 2 to a tryptophan (22), which resulted in a fivefold loss of affinity, for the free peptide when compared with the MBP fusion. RESULTS |
|
207 209 22 chemical In general, there was good agreement between the respective binding affinities of the synthesized peptides and their MBP fusion counterparts, except for substitution of valine at position 2 to a tryptophan (22), which resulted in a fivefold loss of affinity, for the free peptide when compared with the MBP fusion. RESULTS |
|
249 257 affinity evidence In general, there was good agreement between the respective binding affinities of the synthesized peptides and their MBP fusion counterparts, except for substitution of valine at position 2 to a tryptophan (22), which resulted in a fivefold loss of affinity, for the free peptide when compared with the MBP fusion. RESULTS |
|
303 313 MBP fusion experimental_method In general, there was good agreement between the respective binding affinities of the synthesized peptides and their MBP fusion counterparts, except for substitution of valine at position 2 to a tryptophan (22), which resulted in a fivefold loss of affinity, for the free peptide when compared with the MBP fusion. RESULTS |
|
52 55 SAR experimental_method Combining the key amino-acid residues identified by SAR into a single peptide sequence resulted in peptide 30, named high affinity peptide (HAP), that was found to inhibit IL-17A signaling in a BJ human fibroblast cell assay with an IC50 of 17 nM, a more than 20-fold improvement over the phage peptide 1 (Table 2 and Supplementary Figure S2). RESULTS |
|
99 109 peptide 30 chemical Combining the key amino-acid residues identified by SAR into a single peptide sequence resulted in peptide 30, named high affinity peptide (HAP), that was found to inhibit IL-17A signaling in a BJ human fibroblast cell assay with an IC50 of 17 nM, a more than 20-fold improvement over the phage peptide 1 (Table 2 and Supplementary Figure S2). RESULTS |
|
117 138 high affinity peptide chemical Combining the key amino-acid residues identified by SAR into a single peptide sequence resulted in peptide 30, named high affinity peptide (HAP), that was found to inhibit IL-17A signaling in a BJ human fibroblast cell assay with an IC50 of 17 nM, a more than 20-fold improvement over the phage peptide 1 (Table 2 and Supplementary Figure S2). RESULTS |
|
140 143 HAP chemical Combining the key amino-acid residues identified by SAR into a single peptide sequence resulted in peptide 30, named high affinity peptide (HAP), that was found to inhibit IL-17A signaling in a BJ human fibroblast cell assay with an IC50 of 17 nM, a more than 20-fold improvement over the phage peptide 1 (Table 2 and Supplementary Figure S2). RESULTS |
|
172 178 IL-17A protein Combining the key amino-acid residues identified by SAR into a single peptide sequence resulted in peptide 30, named high affinity peptide (HAP), that was found to inhibit IL-17A signaling in a BJ human fibroblast cell assay with an IC50 of 17 nM, a more than 20-fold improvement over the phage peptide 1 (Table 2 and Supplementary Figure S2). RESULTS |
|
197 202 human species Combining the key amino-acid residues identified by SAR into a single peptide sequence resulted in peptide 30, named high affinity peptide (HAP), that was found to inhibit IL-17A signaling in a BJ human fibroblast cell assay with an IC50 of 17 nM, a more than 20-fold improvement over the phage peptide 1 (Table 2 and Supplementary Figure S2). RESULTS |
|
233 237 IC50 evidence Combining the key amino-acid residues identified by SAR into a single peptide sequence resulted in peptide 30, named high affinity peptide (HAP), that was found to inhibit IL-17A signaling in a BJ human fibroblast cell assay with an IC50 of 17 nM, a more than 20-fold improvement over the phage peptide 1 (Table 2 and Supplementary Figure S2). RESULTS |
|
289 294 phage experimental_method Combining the key amino-acid residues identified by SAR into a single peptide sequence resulted in peptide 30, named high affinity peptide (HAP), that was found to inhibit IL-17A signaling in a BJ human fibroblast cell assay with an IC50 of 17 nM, a more than 20-fold improvement over the phage peptide 1 (Table 2 and Supplementary Figure S2). RESULTS |
|
295 304 peptide 1 chemical Combining the key amino-acid residues identified by SAR into a single peptide sequence resulted in peptide 30, named high affinity peptide (HAP), that was found to inhibit IL-17A signaling in a BJ human fibroblast cell assay with an IC50 of 17 nM, a more than 20-fold improvement over the phage peptide 1 (Table 2 and Supplementary Figure S2). RESULTS |
|
78 81 HAP chemical We also examined the effect of removing the acetyl group at the N-terminus of HAP (which is present in all the peptides made, see Supplementary Material). RESULTS |
|
4 13 un-capped protein_state The un-capped peptide (31) had an IC50 of 420 nM in the cell-based assay. RESULTS |
|
14 26 peptide (31) chemical The un-capped peptide (31) had an IC50 of 420 nM in the cell-based assay. RESULTS |
|
34 38 IC50 evidence The un-capped peptide (31) had an IC50 of 420 nM in the cell-based assay. RESULTS |
|
56 72 cell-based assay experimental_method The un-capped peptide (31) had an IC50 of 420 nM in the cell-based assay. RESULTS |
|
33 35 31 chemical The loss of cellular activity of 31 was most likely due to the degradation of the N-terminus of 31, since peptide 31 was shown to be able to bind to IL-17A with similar affinity as HAP itself. RESULTS |
|
96 98 31 chemical The loss of cellular activity of 31 was most likely due to the degradation of the N-terminus of 31, since peptide 31 was shown to be able to bind to IL-17A with similar affinity as HAP itself. RESULTS |
|
114 116 31 chemical The loss of cellular activity of 31 was most likely due to the degradation of the N-terminus of 31, since peptide 31 was shown to be able to bind to IL-17A with similar affinity as HAP itself. RESULTS |
|
149 155 IL-17A protein The loss of cellular activity of 31 was most likely due to the degradation of the N-terminus of 31, since peptide 31 was shown to be able to bind to IL-17A with similar affinity as HAP itself. RESULTS |
|
181 184 HAP chemical The loss of cellular activity of 31 was most likely due to the degradation of the N-terminus of 31, since peptide 31 was shown to be able to bind to IL-17A with similar affinity as HAP itself. RESULTS |
|
52 68 antibody fusions experimental_method Furthermore, our previous work had reported that in antibody fusions the uncapped peptide was degraded under cell assay conditions with removal of the first 1-3 residues to inactive products with the same N-terminal sequences as peptides 32–34. RESULTS |
|
73 81 uncapped protein_state Furthermore, our previous work had reported that in antibody fusions the uncapped peptide was degraded under cell assay conditions with removal of the first 1-3 residues to inactive products with the same N-terminal sequences as peptides 32–34. RESULTS |
|
82 89 peptide chemical Furthermore, our previous work had reported that in antibody fusions the uncapped peptide was degraded under cell assay conditions with removal of the first 1-3 residues to inactive products with the same N-terminal sequences as peptides 32–34. RESULTS |
|
136 146 removal of experimental_method Furthermore, our previous work had reported that in antibody fusions the uncapped peptide was degraded under cell assay conditions with removal of the first 1-3 residues to inactive products with the same N-terminal sequences as peptides 32–34. RESULTS |
|
151 169 first 1-3 residues residue_range Furthermore, our previous work had reported that in antibody fusions the uncapped peptide was degraded under cell assay conditions with removal of the first 1-3 residues to inactive products with the same N-terminal sequences as peptides 32–34. RESULTS |
|
229 243 peptides 32–34 chemical Furthermore, our previous work had reported that in antibody fusions the uncapped peptide was degraded under cell assay conditions with removal of the first 1-3 residues to inactive products with the same N-terminal sequences as peptides 32–34. RESULTS |
|
14 19 32–34 chemical In this work, 32–34 are capped by protective acetyl group and reflect the same inactivity as reported. RESULTS |
|
24 30 capped protein_state In this work, 32–34 are capped by protective acetyl group and reflect the same inactivity as reported. RESULTS |
|
11 22 truncations experimental_method C-terminal truncations showed a more gradual reduction in activity (35–37 |
|
68 73 35–37 chemical C-terminal truncations showed a more gradual reduction in activity (35–37 |
|
6 17 deletion of experimental_method After deletion of three amino acids from the C-terminal end (37), the peptide is no longer active. RESULTS |
|
18 35 three amino acids residue_range After deletion of three amino acids from the C-terminal end (37), the peptide is no longer active. RESULTS |
|
61 63 37 chemical After deletion of three amino acids from the C-terminal end (37), the peptide is no longer active. RESULTS |
|
16 19 HAP chemical Dimerization of HAP can further increase its potency RESULTS |
|
27 33 IL-17A protein We reasoned that since the IL-17A protein is almost exclusively present in a dimeric form, dimerizing the IL-17A binding peptides could result in an improvement in binding affinity and inhibitory activity. RESULTS |
|
77 84 dimeric oligomeric_state We reasoned that since the IL-17A protein is almost exclusively present in a dimeric form, dimerizing the IL-17A binding peptides could result in an improvement in binding affinity and inhibitory activity. RESULTS |
|
91 101 dimerizing oligomeric_state We reasoned that since the IL-17A protein is almost exclusively present in a dimeric form, dimerizing the IL-17A binding peptides could result in an improvement in binding affinity and inhibitory activity. RESULTS |
|
106 112 IL-17A protein We reasoned that since the IL-17A protein is almost exclusively present in a dimeric form, dimerizing the IL-17A binding peptides could result in an improvement in binding affinity and inhibitory activity. RESULTS |
|
164 180 binding affinity evidence We reasoned that since the IL-17A protein is almost exclusively present in a dimeric form, dimerizing the IL-17A binding peptides could result in an improvement in binding affinity and inhibitory activity. RESULTS |
|
0 10 Homodimers oligomeric_state Homodimers of HAP were made through attachment of polyethylene glycol (PEG) spacers of different lengths at amino acids 4, 7 and 14, as these positions were identified in the alanine scan analysis as not contributing significantly to the activity, and at each N-terminus (Supplementary Table S2). RESULTS |
|
14 17 HAP chemical Homodimers of HAP were made through attachment of polyethylene glycol (PEG) spacers of different lengths at amino acids 4, 7 and 14, as these positions were identified in the alanine scan analysis as not contributing significantly to the activity, and at each N-terminus (Supplementary Table S2). RESULTS |
|
50 69 polyethylene glycol chemical Homodimers of HAP were made through attachment of polyethylene glycol (PEG) spacers of different lengths at amino acids 4, 7 and 14, as these positions were identified in the alanine scan analysis as not contributing significantly to the activity, and at each N-terminus (Supplementary Table S2). RESULTS |
|
71 74 PEG chemical Homodimers of HAP were made through attachment of polyethylene glycol (PEG) spacers of different lengths at amino acids 4, 7 and 14, as these positions were identified in the alanine scan analysis as not contributing significantly to the activity, and at each N-terminus (Supplementary Table S2). RESULTS |
|
120 121 4 residue_number Homodimers of HAP were made through attachment of polyethylene glycol (PEG) spacers of different lengths at amino acids 4, 7 and 14, as these positions were identified in the alanine scan analysis as not contributing significantly to the activity, and at each N-terminus (Supplementary Table S2). RESULTS |
|
123 124 7 residue_number Homodimers of HAP were made through attachment of polyethylene glycol (PEG) spacers of different lengths at amino acids 4, 7 and 14, as these positions were identified in the alanine scan analysis as not contributing significantly to the activity, and at each N-terminus (Supplementary Table S2). RESULTS |
|
129 131 14 residue_number Homodimers of HAP were made through attachment of polyethylene glycol (PEG) spacers of different lengths at amino acids 4, 7 and 14, as these positions were identified in the alanine scan analysis as not contributing significantly to the activity, and at each N-terminus (Supplementary Table S2). RESULTS |
|
175 196 alanine scan analysis experimental_method Homodimers of HAP were made through attachment of polyethylene glycol (PEG) spacers of different lengths at amino acids 4, 7 and 14, as these positions were identified in the alanine scan analysis as not contributing significantly to the activity, and at each N-terminus (Supplementary Table S2). RESULTS |
|
34 50 pentafluoroester chemical Due to the high reactivity of the pentafluoroester (PFP) group used as the activating group in the PEG, the histidine at position 2 and the lysine at position 15 were replaced with threonine and dimethyllysine respectively to prevent formation of side products, which resulted in peptide 38 that was comparable in activity with HAP. RESULTS |
|
52 55 PFP chemical Due to the high reactivity of the pentafluoroester (PFP) group used as the activating group in the PEG, the histidine at position 2 and the lysine at position 15 were replaced with threonine and dimethyllysine respectively to prevent formation of side products, which resulted in peptide 38 that was comparable in activity with HAP. RESULTS |
|
99 102 PEG chemical Due to the high reactivity of the pentafluoroester (PFP) group used as the activating group in the PEG, the histidine at position 2 and the lysine at position 15 were replaced with threonine and dimethyllysine respectively to prevent formation of side products, which resulted in peptide 38 that was comparable in activity with HAP. RESULTS |
|
108 117 histidine residue_name Due to the high reactivity of the pentafluoroester (PFP) group used as the activating group in the PEG, the histidine at position 2 and the lysine at position 15 were replaced with threonine and dimethyllysine respectively to prevent formation of side products, which resulted in peptide 38 that was comparable in activity with HAP. RESULTS |
|
130 131 2 residue_number Due to the high reactivity of the pentafluoroester (PFP) group used as the activating group in the PEG, the histidine at position 2 and the lysine at position 15 were replaced with threonine and dimethyllysine respectively to prevent formation of side products, which resulted in peptide 38 that was comparable in activity with HAP. RESULTS |
|
140 146 lysine residue_name Due to the high reactivity of the pentafluoroester (PFP) group used as the activating group in the PEG, the histidine at position 2 and the lysine at position 15 were replaced with threonine and dimethyllysine respectively to prevent formation of side products, which resulted in peptide 38 that was comparable in activity with HAP. RESULTS |
|
159 161 15 residue_number Due to the high reactivity of the pentafluoroester (PFP) group used as the activating group in the PEG, the histidine at position 2 and the lysine at position 15 were replaced with threonine and dimethyllysine respectively to prevent formation of side products, which resulted in peptide 38 that was comparable in activity with HAP. RESULTS |
|
181 190 threonine residue_name Due to the high reactivity of the pentafluoroester (PFP) group used as the activating group in the PEG, the histidine at position 2 and the lysine at position 15 were replaced with threonine and dimethyllysine respectively to prevent formation of side products, which resulted in peptide 38 that was comparable in activity with HAP. RESULTS |
|
195 209 dimethyllysine residue_name Due to the high reactivity of the pentafluoroester (PFP) group used as the activating group in the PEG, the histidine at position 2 and the lysine at position 15 were replaced with threonine and dimethyllysine respectively to prevent formation of side products, which resulted in peptide 38 that was comparable in activity with HAP. RESULTS |
|
280 290 peptide 38 chemical Due to the high reactivity of the pentafluoroester (PFP) group used as the activating group in the PEG, the histidine at position 2 and the lysine at position 15 were replaced with threonine and dimethyllysine respectively to prevent formation of side products, which resulted in peptide 38 that was comparable in activity with HAP. RESULTS |
|
328 331 HAP chemical Due to the high reactivity of the pentafluoroester (PFP) group used as the activating group in the PEG, the histidine at position 2 and the lysine at position 15 were replaced with threonine and dimethyllysine respectively to prevent formation of side products, which resulted in peptide 38 that was comparable in activity with HAP. RESULTS |
|
36 43 dimeric oligomeric_state This exercise revealed that several dimeric peptides with the longer PEG21 spacer were significantly more potent than the monomer peptide in the cell-based assay (Supplementary Table S2). RESULTS |
|
44 52 peptides chemical This exercise revealed that several dimeric peptides with the longer PEG21 spacer were significantly more potent than the monomer peptide in the cell-based assay (Supplementary Table S2). RESULTS |
|
69 74 PEG21 chemical This exercise revealed that several dimeric peptides with the longer PEG21 spacer were significantly more potent than the monomer peptide in the cell-based assay (Supplementary Table S2). RESULTS |
|
122 129 monomer oligomeric_state This exercise revealed that several dimeric peptides with the longer PEG21 spacer were significantly more potent than the monomer peptide in the cell-based assay (Supplementary Table S2). RESULTS |
|
145 161 cell-based assay experimental_method This exercise revealed that several dimeric peptides with the longer PEG21 spacer were significantly more potent than the monomer peptide in the cell-based assay (Supplementary Table S2). RESULTS |
|
0 10 Peptide 45 chemical Peptide 45, dimerized via attachment of a PEG21 spacer at position 14 (Supplementary Scheme S1 and Figure S3), was the most potent with cellular IC50 of 0.1 nM. This significant improvement in antagonism was not seen in the peptide monomer functionalized with a PEG21 group at position 14 as peptide 48 had an IC50 of 21 nM (Supplementary Scheme S2). RESULTS |
|
12 21 dimerized oligomeric_state Peptide 45, dimerized via attachment of a PEG21 spacer at position 14 (Supplementary Scheme S1 and Figure S3), was the most potent with cellular IC50 of 0.1 nM. This significant improvement in antagonism was not seen in the peptide monomer functionalized with a PEG21 group at position 14 as peptide 48 had an IC50 of 21 nM (Supplementary Scheme S2). RESULTS |
|
42 47 PEG21 chemical Peptide 45, dimerized via attachment of a PEG21 spacer at position 14 (Supplementary Scheme S1 and Figure S3), was the most potent with cellular IC50 of 0.1 nM. This significant improvement in antagonism was not seen in the peptide monomer functionalized with a PEG21 group at position 14 as peptide 48 had an IC50 of 21 nM (Supplementary Scheme S2). RESULTS |
|
67 69 14 residue_number Peptide 45, dimerized via attachment of a PEG21 spacer at position 14 (Supplementary Scheme S1 and Figure S3), was the most potent with cellular IC50 of 0.1 nM. This significant improvement in antagonism was not seen in the peptide monomer functionalized with a PEG21 group at position 14 as peptide 48 had an IC50 of 21 nM (Supplementary Scheme S2). RESULTS |
|
145 149 IC50 evidence Peptide 45, dimerized via attachment of a PEG21 spacer at position 14 (Supplementary Scheme S1 and Figure S3), was the most potent with cellular IC50 of 0.1 nM. This significant improvement in antagonism was not seen in the peptide monomer functionalized with a PEG21 group at position 14 as peptide 48 had an IC50 of 21 nM (Supplementary Scheme S2). RESULTS |
|
232 239 monomer oligomeric_state Peptide 45, dimerized via attachment of a PEG21 spacer at position 14 (Supplementary Scheme S1 and Figure S3), was the most potent with cellular IC50 of 0.1 nM. This significant improvement in antagonism was not seen in the peptide monomer functionalized with a PEG21 group at position 14 as peptide 48 had an IC50 of 21 nM (Supplementary Scheme S2). RESULTS |
|
262 267 PEG21 chemical Peptide 45, dimerized via attachment of a PEG21 spacer at position 14 (Supplementary Scheme S1 and Figure S3), was the most potent with cellular IC50 of 0.1 nM. This significant improvement in antagonism was not seen in the peptide monomer functionalized with a PEG21 group at position 14 as peptide 48 had an IC50 of 21 nM (Supplementary Scheme S2). RESULTS |
|
286 288 14 residue_number Peptide 45, dimerized via attachment of a PEG21 spacer at position 14 (Supplementary Scheme S1 and Figure S3), was the most potent with cellular IC50 of 0.1 nM. This significant improvement in antagonism was not seen in the peptide monomer functionalized with a PEG21 group at position 14 as peptide 48 had an IC50 of 21 nM (Supplementary Scheme S2). RESULTS |
|
292 302 peptide 48 chemical Peptide 45, dimerized via attachment of a PEG21 spacer at position 14 (Supplementary Scheme S1 and Figure S3), was the most potent with cellular IC50 of 0.1 nM. This significant improvement in antagonism was not seen in the peptide monomer functionalized with a PEG21 group at position 14 as peptide 48 had an IC50 of 21 nM (Supplementary Scheme S2). RESULTS |
|
310 314 IC50 evidence Peptide 45, dimerized via attachment of a PEG21 spacer at position 14 (Supplementary Scheme S1 and Figure S3), was the most potent with cellular IC50 of 0.1 nM. This significant improvement in antagonism was not seen in the peptide monomer functionalized with a PEG21 group at position 14 as peptide 48 had an IC50 of 21 nM (Supplementary Scheme S2). RESULTS |
|
36 43 dimeric oligomeric_state The species cross-reactivity of the dimeric peptide 45 and HAP were assessed in a murine functional cell assay using 15 ng/ml murine IL-17A. RESULTS |
|
44 54 peptide 45 chemical The species cross-reactivity of the dimeric peptide 45 and HAP were assessed in a murine functional cell assay using 15 ng/ml murine IL-17A. RESULTS |
|
59 62 HAP chemical The species cross-reactivity of the dimeric peptide 45 and HAP were assessed in a murine functional cell assay using 15 ng/ml murine IL-17A. RESULTS |
|
82 110 murine functional cell assay experimental_method The species cross-reactivity of the dimeric peptide 45 and HAP were assessed in a murine functional cell assay using 15 ng/ml murine IL-17A. RESULTS |
|
126 132 murine taxonomy_domain The species cross-reactivity of the dimeric peptide 45 and HAP were assessed in a murine functional cell assay using 15 ng/ml murine IL-17A. RESULTS |
|
133 139 IL-17A protein The species cross-reactivity of the dimeric peptide 45 and HAP were assessed in a murine functional cell assay using 15 ng/ml murine IL-17A. RESULTS |
|
0 10 Peptide 45 chemical Peptide 45 blocked the receptor binding of murine IL-17A although with potency two orders of magnitude weaker than that observed against human IL-17A (IC50 = 41 nM vs IC50 = 0.1 nM, respectively). RESULTS |
|
23 31 receptor protein_type Peptide 45 blocked the receptor binding of murine IL-17A although with potency two orders of magnitude weaker than that observed against human IL-17A (IC50 = 41 nM vs IC50 = 0.1 nM, respectively). RESULTS |
|
43 49 murine taxonomy_domain Peptide 45 blocked the receptor binding of murine IL-17A although with potency two orders of magnitude weaker than that observed against human IL-17A (IC50 = 41 nM vs IC50 = 0.1 nM, respectively). RESULTS |
|
50 56 IL-17A protein Peptide 45 blocked the receptor binding of murine IL-17A although with potency two orders of magnitude weaker than that observed against human IL-17A (IC50 = 41 nM vs IC50 = 0.1 nM, respectively). RESULTS |
|
137 142 human species Peptide 45 blocked the receptor binding of murine IL-17A although with potency two orders of magnitude weaker than that observed against human IL-17A (IC50 = 41 nM vs IC50 = 0.1 nM, respectively). RESULTS |
|
143 149 IL-17A protein Peptide 45 blocked the receptor binding of murine IL-17A although with potency two orders of magnitude weaker than that observed against human IL-17A (IC50 = 41 nM vs IC50 = 0.1 nM, respectively). RESULTS |
|
151 155 IC50 evidence Peptide 45 blocked the receptor binding of murine IL-17A although with potency two orders of magnitude weaker than that observed against human IL-17A (IC50 = 41 nM vs IC50 = 0.1 nM, respectively). RESULTS |
|
167 171 IC50 evidence Peptide 45 blocked the receptor binding of murine IL-17A although with potency two orders of magnitude weaker than that observed against human IL-17A (IC50 = 41 nM vs IC50 = 0.1 nM, respectively). RESULTS |
|
4 11 monomer oligomeric_state The monomer HAP was much weaker (IC50 >1 μM) in inhibiting murine IL-17A signaling (Supplementary Figure S4). RESULTS |
|
12 15 HAP chemical The monomer HAP was much weaker (IC50 >1 μM) in inhibiting murine IL-17A signaling (Supplementary Figure S4). RESULTS |
|
33 37 IC50 evidence The monomer HAP was much weaker (IC50 >1 μM) in inhibiting murine IL-17A signaling (Supplementary Figure S4). RESULTS |
|
59 65 murine taxonomy_domain The monomer HAP was much weaker (IC50 >1 μM) in inhibiting murine IL-17A signaling (Supplementary Figure S4). RESULTS |
|
66 72 IL-17A protein The monomer HAP was much weaker (IC50 >1 μM) in inhibiting murine IL-17A signaling (Supplementary Figure S4). RESULTS |
|
13 20 dimeric oligomeric_state Although the dimeric peptide 45 is much more potent than HAP in the cell-based assay, in subsequent studies we decided to focus our efforts solely on characterizations of the monomeric peptide HAP in hopes to identify smaller peptide inhibitors containing the best minimal functional group. RESULTS |
|
21 31 peptide 45 chemical Although the dimeric peptide 45 is much more potent than HAP in the cell-based assay, in subsequent studies we decided to focus our efforts solely on characterizations of the monomeric peptide HAP in hopes to identify smaller peptide inhibitors containing the best minimal functional group. RESULTS |
|
57 60 HAP chemical Although the dimeric peptide 45 is much more potent than HAP in the cell-based assay, in subsequent studies we decided to focus our efforts solely on characterizations of the monomeric peptide HAP in hopes to identify smaller peptide inhibitors containing the best minimal functional group. RESULTS |
|
68 84 cell-based assay experimental_method Although the dimeric peptide 45 is much more potent than HAP in the cell-based assay, in subsequent studies we decided to focus our efforts solely on characterizations of the monomeric peptide HAP in hopes to identify smaller peptide inhibitors containing the best minimal functional group. RESULTS |
|
175 184 monomeric oligomeric_state Although the dimeric peptide 45 is much more potent than HAP in the cell-based assay, in subsequent studies we decided to focus our efforts solely on characterizations of the monomeric peptide HAP in hopes to identify smaller peptide inhibitors containing the best minimal functional group. RESULTS |
|
193 196 HAP chemical Although the dimeric peptide 45 is much more potent than HAP in the cell-based assay, in subsequent studies we decided to focus our efforts solely on characterizations of the monomeric peptide HAP in hopes to identify smaller peptide inhibitors containing the best minimal functional group. RESULTS |
|
29 32 HAP chemical Orthogonal assays to confirm HAP antagonism RESULTS |
|
43 46 HAP chemical To further characterize the interaction of HAP with IL-17A, we set out to determine its in vitro binding affinity, specificity and kinetic profile using Surface Plasmon Resonance (SPR) methods (Fig. 1A). RESULTS |
|
52 58 IL-17A protein To further characterize the interaction of HAP with IL-17A, we set out to determine its in vitro binding affinity, specificity and kinetic profile using Surface Plasmon Resonance (SPR) methods (Fig. 1A). RESULTS |
|
97 113 binding affinity evidence To further characterize the interaction of HAP with IL-17A, we set out to determine its in vitro binding affinity, specificity and kinetic profile using Surface Plasmon Resonance (SPR) methods (Fig. 1A). RESULTS |
|
131 146 kinetic profile evidence To further characterize the interaction of HAP with IL-17A, we set out to determine its in vitro binding affinity, specificity and kinetic profile using Surface Plasmon Resonance (SPR) methods (Fig. 1A). RESULTS |
|
153 178 Surface Plasmon Resonance experimental_method To further characterize the interaction of HAP with IL-17A, we set out to determine its in vitro binding affinity, specificity and kinetic profile using Surface Plasmon Resonance (SPR) methods (Fig. 1A). RESULTS |
|
180 183 SPR experimental_method To further characterize the interaction of HAP with IL-17A, we set out to determine its in vitro binding affinity, specificity and kinetic profile using Surface Plasmon Resonance (SPR) methods (Fig. 1A). RESULTS |
|
0 3 HAP chemical HAP binds to immobilized human IL-17A homodimer tightly (Table 3). RESULTS |
|
25 30 human species HAP binds to immobilized human IL-17A homodimer tightly (Table 3). RESULTS |
|
31 37 IL-17A protein HAP binds to immobilized human IL-17A homodimer tightly (Table 3). RESULTS |
|
38 47 homodimer oligomeric_state HAP binds to immobilized human IL-17A homodimer tightly (Table 3). RESULTS |
|
23 31 affinity evidence It has slightly weaker affinity for human IL-17A/F heterodimer and >10 fold weaker affinity for mouse IL-17A (Table 3). RESULTS |
|
36 41 human species It has slightly weaker affinity for human IL-17A/F heterodimer and >10 fold weaker affinity for mouse IL-17A (Table 3). RESULTS |
|
42 50 IL-17A/F complex_assembly It has slightly weaker affinity for human IL-17A/F heterodimer and >10 fold weaker affinity for mouse IL-17A (Table 3). RESULTS |
|
51 62 heterodimer oligomeric_state It has slightly weaker affinity for human IL-17A/F heterodimer and >10 fold weaker affinity for mouse IL-17A (Table 3). RESULTS |
|
83 91 affinity evidence It has slightly weaker affinity for human IL-17A/F heterodimer and >10 fold weaker affinity for mouse IL-17A (Table 3). RESULTS |
|
96 101 mouse taxonomy_domain It has slightly weaker affinity for human IL-17A/F heterodimer and >10 fold weaker affinity for mouse IL-17A (Table 3). RESULTS |
|
102 108 IL-17A protein It has slightly weaker affinity for human IL-17A/F heterodimer and >10 fold weaker affinity for mouse IL-17A (Table 3). RESULTS |
|
0 3 HAP chemical HAP does not show significant binding to immobilized human IL-17F homodimer or IL-17RA at concentrations up to 100 nM. RESULTS |
|
53 58 human species HAP does not show significant binding to immobilized human IL-17F homodimer or IL-17RA at concentrations up to 100 nM. RESULTS |
|
59 65 IL-17F protein HAP does not show significant binding to immobilized human IL-17F homodimer or IL-17RA at concentrations up to 100 nM. RESULTS |
|
66 75 homodimer oligomeric_state HAP does not show significant binding to immobilized human IL-17F homodimer or IL-17RA at concentrations up to 100 nM. RESULTS |
|
79 86 IL-17RA protein HAP does not show significant binding to immobilized human IL-17F homodimer or IL-17RA at concentrations up to 100 nM. RESULTS |
|
52 57 human species Additionally, we investigated the antagonism of the human IL-17A/IL-17RA interaction by HAP using orthogonal methods including SPR and Förster resonance energy transfer (FRET) competition assays (Fig. 1B,C). RESULTS |
|
58 72 IL-17A/IL-17RA complex_assembly Additionally, we investigated the antagonism of the human IL-17A/IL-17RA interaction by HAP using orthogonal methods including SPR and Förster resonance energy transfer (FRET) competition assays (Fig. 1B,C). RESULTS |
|
88 91 HAP chemical Additionally, we investigated the antagonism of the human IL-17A/IL-17RA interaction by HAP using orthogonal methods including SPR and Förster resonance energy transfer (FRET) competition assays (Fig. 1B,C). RESULTS |
|
127 130 SPR experimental_method Additionally, we investigated the antagonism of the human IL-17A/IL-17RA interaction by HAP using orthogonal methods including SPR and Förster resonance energy transfer (FRET) competition assays (Fig. 1B,C). RESULTS |
|
135 194 Förster resonance energy transfer (FRET) competition assays experimental_method Additionally, we investigated the antagonism of the human IL-17A/IL-17RA interaction by HAP using orthogonal methods including SPR and Förster resonance energy transfer (FRET) competition assays (Fig. 1B,C). RESULTS |
|
30 36 IL-17A protein In both assays, incubation of IL-17A with HAP effectively blocks the binding of IL-17A to immobilized IL-17RA with similar sub-nM IC50 (Table 3). RESULTS |
|
42 45 HAP chemical In both assays, incubation of IL-17A with HAP effectively blocks the binding of IL-17A to immobilized IL-17RA with similar sub-nM IC50 (Table 3). RESULTS |
|
80 86 IL-17A protein In both assays, incubation of IL-17A with HAP effectively blocks the binding of IL-17A to immobilized IL-17RA with similar sub-nM IC50 (Table 3). RESULTS |
|
90 101 immobilized protein_state In both assays, incubation of IL-17A with HAP effectively blocks the binding of IL-17A to immobilized IL-17RA with similar sub-nM IC50 (Table 3). RESULTS |
|
102 109 IL-17RA protein In both assays, incubation of IL-17A with HAP effectively blocks the binding of IL-17A to immobilized IL-17RA with similar sub-nM IC50 (Table 3). RESULTS |
|
130 134 IC50 evidence In both assays, incubation of IL-17A with HAP effectively blocks the binding of IL-17A to immobilized IL-17RA with similar sub-nM IC50 (Table 3). RESULTS |
|
0 3 HAP chemical HAP blocks IL-17A signaling in a human primary cell assay RESULTS |
|
11 17 IL-17A protein HAP blocks IL-17A signaling in a human primary cell assay RESULTS |
|
33 38 human species HAP blocks IL-17A signaling in a human primary cell assay RESULTS |
|
13 19 IL-17A protein While either IL-17A or TNF-α alone can stimulate the release of multiple inflammatory cytokines, when acting together they can synergistically enhance each other’s effects (Supplementary Figure S5). RESULTS |
|
23 28 TNF-α protein While either IL-17A or TNF-α alone can stimulate the release of multiple inflammatory cytokines, when acting together they can synergistically enhance each other’s effects (Supplementary Figure S5). RESULTS |
|
86 95 cytokines protein_type While either IL-17A or TNF-α alone can stimulate the release of multiple inflammatory cytokines, when acting together they can synergistically enhance each other’s effects (Supplementary Figure S5). RESULTS |
|
31 37 IL-17A protein These integrative responses to IL-17A and TNF-α in human keratinocytes have been reported to account for key inflammatory pathogenic circuits in psoriasis. RESULTS |
|
42 47 TNF-α protein These integrative responses to IL-17A and TNF-α in human keratinocytes have been reported to account for key inflammatory pathogenic circuits in psoriasis. RESULTS |
|
51 56 human species These integrative responses to IL-17A and TNF-α in human keratinocytes have been reported to account for key inflammatory pathogenic circuits in psoriasis. RESULTS |
|
24 27 HAP chemical Thus, we chose to study HAP’s efficacy in blocking the production of IL-8, IL-6 and CCL-20 by primary human keratinocytes stimulated by IL-17A in the presence of TNF-α, an assay which may be more disease-relevant. RESULTS |
|
69 73 IL-8 protein_type Thus, we chose to study HAP’s efficacy in blocking the production of IL-8, IL-6 and CCL-20 by primary human keratinocytes stimulated by IL-17A in the presence of TNF-α, an assay which may be more disease-relevant. RESULTS |
|
75 79 IL-6 protein_type Thus, we chose to study HAP’s efficacy in blocking the production of IL-8, IL-6 and CCL-20 by primary human keratinocytes stimulated by IL-17A in the presence of TNF-α, an assay which may be more disease-relevant. RESULTS |
|
84 90 CCL-20 protein_type Thus, we chose to study HAP’s efficacy in blocking the production of IL-8, IL-6 and CCL-20 by primary human keratinocytes stimulated by IL-17A in the presence of TNF-α, an assay which may be more disease-relevant. RESULTS |
|
102 107 human species Thus, we chose to study HAP’s efficacy in blocking the production of IL-8, IL-6 and CCL-20 by primary human keratinocytes stimulated by IL-17A in the presence of TNF-α, an assay which may be more disease-relevant. RESULTS |
|
136 142 IL-17A protein Thus, we chose to study HAP’s efficacy in blocking the production of IL-8, IL-6 and CCL-20 by primary human keratinocytes stimulated by IL-17A in the presence of TNF-α, an assay which may be more disease-relevant. RESULTS |
|
162 167 TNF-α protein Thus, we chose to study HAP’s efficacy in blocking the production of IL-8, IL-6 and CCL-20 by primary human keratinocytes stimulated by IL-17A in the presence of TNF-α, an assay which may be more disease-relevant. RESULTS |
|
0 3 HAP chemical HAP inhibits the production of all three cytokines in a dose-dependent fashion (Fig. 1D). RESULTS |
|
41 50 cytokines protein_type HAP inhibits the production of all three cytokines in a dose-dependent fashion (Fig. 1D). RESULTS |
|
38 42 IL-8 protein_type Significantly, the baseline levels of IL-8, IL-6 and CCL-20 stimulated by TNF-α alone are not inhibited by HAP, further indicating the selectivity of HAP (Fig. 1D). RESULTS |
|
44 48 IL-6 protein_type Significantly, the baseline levels of IL-8, IL-6 and CCL-20 stimulated by TNF-α alone are not inhibited by HAP, further indicating the selectivity of HAP (Fig. 1D). RESULTS |
|
53 59 CCL-20 protein_type Significantly, the baseline levels of IL-8, IL-6 and CCL-20 stimulated by TNF-α alone are not inhibited by HAP, further indicating the selectivity of HAP (Fig. 1D). RESULTS |
|
74 79 TNF-α protein Significantly, the baseline levels of IL-8, IL-6 and CCL-20 stimulated by TNF-α alone are not inhibited by HAP, further indicating the selectivity of HAP (Fig. 1D). RESULTS |
|
107 110 HAP chemical Significantly, the baseline levels of IL-8, IL-6 and CCL-20 stimulated by TNF-α alone are not inhibited by HAP, further indicating the selectivity of HAP (Fig. 1D). RESULTS |
|
150 153 HAP chemical Significantly, the baseline levels of IL-8, IL-6 and CCL-20 stimulated by TNF-α alone are not inhibited by HAP, further indicating the selectivity of HAP (Fig. 1D). RESULTS |
|
172 177 TNF-α protein Such pharmacological selectivity may be important to suppress inflammatory pathogenic circuits in psoriasis, while sparing the anti-infectious immune responses produced by TNF-α. RESULTS |
|
20 24 IC50 evidence The relatively high IC50 values in this assay (Table 3) are probably due to the high IL-17A concentration (100 ng/ml) needed for detection of IL-6. RESULTS |
|
85 91 IL-17A protein The relatively high IC50 values in this assay (Table 3) are probably due to the high IL-17A concentration (100 ng/ml) needed for detection of IL-6. RESULTS |
|
142 146 IL-6 protein_type The relatively high IC50 values in this assay (Table 3) are probably due to the high IL-17A concentration (100 ng/ml) needed for detection of IL-6. RESULTS |
|
34 40 IL-17A protein As a reference, a commercial anti-IL-17A antibody (R&D Systems) inhibits the production of IL-8 with an IC50 of 13(±6) nM (N = 3). RESULTS |
|
41 49 antibody protein_type As a reference, a commercial anti-IL-17A antibody (R&D Systems) inhibits the production of IL-8 with an IC50 of 13(±6) nM (N = 3). RESULTS |
|
91 95 IL-8 protein_type As a reference, a commercial anti-IL-17A antibody (R&D Systems) inhibits the production of IL-8 with an IC50 of 13(±6) nM (N = 3). RESULTS |
|
104 108 IC50 evidence As a reference, a commercial anti-IL-17A antibody (R&D Systems) inhibits the production of IL-8 with an IC50 of 13(±6) nM (N = 3). RESULTS |
|
12 16 IC50 evidence Indeed, the IC50 was 14(±9) nM (N = 12) for HAP inhibition of IL-8 production when only 5 ng/ml IL-17A was used in this assay. RESULTS |
|
44 47 HAP chemical Indeed, the IC50 was 14(±9) nM (N = 12) for HAP inhibition of IL-8 production when only 5 ng/ml IL-17A was used in this assay. RESULTS |
|
62 66 IL-8 protein_type Indeed, the IC50 was 14(±9) nM (N = 12) for HAP inhibition of IL-8 production when only 5 ng/ml IL-17A was used in this assay. RESULTS |
|
96 102 IL-17A protein Indeed, the IC50 was 14(±9) nM (N = 12) for HAP inhibition of IL-8 production when only 5 ng/ml IL-17A was used in this assay. RESULTS |
|
34 40 IL-17A protein In patients, the concentration of IL-17A in psoriatic lesions is reported to be 0.01 ng/ml, well below the EC50 (5–10ng/ml) of IL-17A induced IL-8 production in vitro. RESULTS |
|
127 133 IL-17A protein In patients, the concentration of IL-17A in psoriatic lesions is reported to be 0.01 ng/ml, well below the EC50 (5–10ng/ml) of IL-17A induced IL-8 production in vitro. RESULTS |
|
142 146 IL-8 protein_type In patients, the concentration of IL-17A in psoriatic lesions is reported to be 0.01 ng/ml, well below the EC50 (5–10ng/ml) of IL-17A induced IL-8 production in vitro. RESULTS |
|
11 30 keratinocytes assay experimental_method Similar to keratinocytes assay results, while HAP inhibits IL-17A stimulated IL-6 production by BJ human fibroblast potently (IC50 of 17 nM), it does not inhibit TNF-α stimulated IL-6 production at concentrations up to 10 μM (Supplementary Figure S2). RESULTS |
|
46 49 HAP chemical Similar to keratinocytes assay results, while HAP inhibits IL-17A stimulated IL-6 production by BJ human fibroblast potently (IC50 of 17 nM), it does not inhibit TNF-α stimulated IL-6 production at concentrations up to 10 μM (Supplementary Figure S2). RESULTS |
|
59 65 IL-17A protein Similar to keratinocytes assay results, while HAP inhibits IL-17A stimulated IL-6 production by BJ human fibroblast potently (IC50 of 17 nM), it does not inhibit TNF-α stimulated IL-6 production at concentrations up to 10 μM (Supplementary Figure S2). RESULTS |
|
77 81 IL-6 protein_type Similar to keratinocytes assay results, while HAP inhibits IL-17A stimulated IL-6 production by BJ human fibroblast potently (IC50 of 17 nM), it does not inhibit TNF-α stimulated IL-6 production at concentrations up to 10 μM (Supplementary Figure S2). RESULTS |
|
99 104 human species Similar to keratinocytes assay results, while HAP inhibits IL-17A stimulated IL-6 production by BJ human fibroblast potently (IC50 of 17 nM), it does not inhibit TNF-α stimulated IL-6 production at concentrations up to 10 μM (Supplementary Figure S2). RESULTS |
|
126 130 IC50 evidence Similar to keratinocytes assay results, while HAP inhibits IL-17A stimulated IL-6 production by BJ human fibroblast potently (IC50 of 17 nM), it does not inhibit TNF-α stimulated IL-6 production at concentrations up to 10 μM (Supplementary Figure S2). RESULTS |
|
162 167 TNF-α protein Similar to keratinocytes assay results, while HAP inhibits IL-17A stimulated IL-6 production by BJ human fibroblast potently (IC50 of 17 nM), it does not inhibit TNF-α stimulated IL-6 production at concentrations up to 10 μM (Supplementary Figure S2). RESULTS |
|
179 183 IL-6 protein_type Similar to keratinocytes assay results, while HAP inhibits IL-17A stimulated IL-6 production by BJ human fibroblast potently (IC50 of 17 nM), it does not inhibit TNF-α stimulated IL-6 production at concentrations up to 10 μM (Supplementary Figure S2). RESULTS |
|
0 43 Crystallization and structure determination experimental_method Crystallization and structure determination RESULTS |
|
10 32 crystallization trials experimental_method Extensive crystallization trials, either by co-crystallization or by soaking HAP into preformed apo IL-17A crystals, failed to lead to an IL-17A/HAP complex crystals. RESULTS |
|
44 62 co-crystallization experimental_method Extensive crystallization trials, either by co-crystallization or by soaking HAP into preformed apo IL-17A crystals, failed to lead to an IL-17A/HAP complex crystals. RESULTS |
|
69 76 soaking experimental_method Extensive crystallization trials, either by co-crystallization or by soaking HAP into preformed apo IL-17A crystals, failed to lead to an IL-17A/HAP complex crystals. RESULTS |
|
77 80 HAP chemical Extensive crystallization trials, either by co-crystallization or by soaking HAP into preformed apo IL-17A crystals, failed to lead to an IL-17A/HAP complex crystals. RESULTS |
|
96 99 apo protein_state Extensive crystallization trials, either by co-crystallization or by soaking HAP into preformed apo IL-17A crystals, failed to lead to an IL-17A/HAP complex crystals. RESULTS |
|
100 106 IL-17A protein Extensive crystallization trials, either by co-crystallization or by soaking HAP into preformed apo IL-17A crystals, failed to lead to an IL-17A/HAP complex crystals. RESULTS |
|
107 115 crystals evidence Extensive crystallization trials, either by co-crystallization or by soaking HAP into preformed apo IL-17A crystals, failed to lead to an IL-17A/HAP complex crystals. RESULTS |
|
138 148 IL-17A/HAP complex_assembly Extensive crystallization trials, either by co-crystallization or by soaking HAP into preformed apo IL-17A crystals, failed to lead to an IL-17A/HAP complex crystals. RESULTS |
|
157 165 crystals evidence Extensive crystallization trials, either by co-crystallization or by soaking HAP into preformed apo IL-17A crystals, failed to lead to an IL-17A/HAP complex crystals. RESULTS |
|
18 21 HAP chemical We theorized that HAP binding induced large conformational changes in IL-17A that led to the difficulty of getting an IL-17A/HAP binary complex crystal. RESULTS |
|
70 76 IL-17A protein We theorized that HAP binding induced large conformational changes in IL-17A that led to the difficulty of getting an IL-17A/HAP binary complex crystal. RESULTS |
|
118 128 IL-17A/HAP complex_assembly We theorized that HAP binding induced large conformational changes in IL-17A that led to the difficulty of getting an IL-17A/HAP binary complex crystal. RESULTS |
|
144 151 crystal evidence We theorized that HAP binding induced large conformational changes in IL-17A that led to the difficulty of getting an IL-17A/HAP binary complex crystal. RESULTS |
|
20 28 antibody protein_type It is known that an antibody antigen-binding fragment (Fab) can be used as crystallization chaperones in crystallizing difficult targets. RESULTS |
|
29 53 antigen-binding fragment structure_element It is known that an antibody antigen-binding fragment (Fab) can be used as crystallization chaperones in crystallizing difficult targets. RESULTS |
|
55 58 Fab structure_element It is known that an antibody antigen-binding fragment (Fab) can be used as crystallization chaperones in crystallizing difficult targets. RESULTS |
|
21 24 HAP chemical We hypothesized that HAP may target the N-terminal of IL-17A which is known to be more flexible than its C-terminal and conformational changes needed for HAP binding may be more likely there. RESULTS |
|
54 60 IL-17A protein We hypothesized that HAP may target the N-terminal of IL-17A which is known to be more flexible than its C-terminal and conformational changes needed for HAP binding may be more likely there. RESULTS |
|
154 157 HAP chemical We hypothesized that HAP may target the N-terminal of IL-17A which is known to be more flexible than its C-terminal and conformational changes needed for HAP binding may be more likely there. RESULTS |
|
15 23 antibody protein_type We designed an antibody Fab known to target the C-terminal half of IL-17A based on a published IL-17A/Fab complex crystal structure, and produced it in HEK293 cells. RESULTS |
|
24 27 Fab structure_element We designed an antibody Fab known to target the C-terminal half of IL-17A based on a published IL-17A/Fab complex crystal structure, and produced it in HEK293 cells. RESULTS |
|
48 63 C-terminal half structure_element We designed an antibody Fab known to target the C-terminal half of IL-17A based on a published IL-17A/Fab complex crystal structure, and produced it in HEK293 cells. RESULTS |
|
67 73 IL-17A protein We designed an antibody Fab known to target the C-terminal half of IL-17A based on a published IL-17A/Fab complex crystal structure, and produced it in HEK293 cells. RESULTS |
|
95 105 IL-17A/Fab complex_assembly We designed an antibody Fab known to target the C-terminal half of IL-17A based on a published IL-17A/Fab complex crystal structure, and produced it in HEK293 cells. RESULTS |
|
114 131 crystal structure evidence We designed an antibody Fab known to target the C-terminal half of IL-17A based on a published IL-17A/Fab complex crystal structure, and produced it in HEK293 cells. RESULTS |
|
6 15 SPR assay experimental_method In an SPR assay HAP and this Fab were able to co-bind IL-17A without large changes in their binding affinities and kinetics, confirming our hypothesis (Supplementary Figure S6). RESULTS |
|
16 19 HAP chemical In an SPR assay HAP and this Fab were able to co-bind IL-17A without large changes in their binding affinities and kinetics, confirming our hypothesis (Supplementary Figure S6). RESULTS |
|
29 32 Fab structure_element In an SPR assay HAP and this Fab were able to co-bind IL-17A without large changes in their binding affinities and kinetics, confirming our hypothesis (Supplementary Figure S6). RESULTS |
|
54 60 IL-17A protein In an SPR assay HAP and this Fab were able to co-bind IL-17A without large changes in their binding affinities and kinetics, confirming our hypothesis (Supplementary Figure S6). RESULTS |
|
92 110 binding affinities evidence In an SPR assay HAP and this Fab were able to co-bind IL-17A without large changes in their binding affinities and kinetics, confirming our hypothesis (Supplementary Figure S6). RESULTS |
|
115 123 kinetics evidence In an SPR assay HAP and this Fab were able to co-bind IL-17A without large changes in their binding affinities and kinetics, confirming our hypothesis (Supplementary Figure S6). RESULTS |
|
61 64 HAP chemical Furthermore, since it binds to an area far away from that of HAP (see below), this Fab should have minimum effects on HAP binding conformation. RESULTS |
|
83 86 Fab structure_element Furthermore, since it binds to an area far away from that of HAP (see below), this Fab should have minimum effects on HAP binding conformation. RESULTS |
|
118 121 HAP chemical Furthermore, since it binds to an area far away from that of HAP (see below), this Fab should have minimum effects on HAP binding conformation. RESULTS |
|
0 8 Crystals evidence Crystals of Fab/IL-17A/HAP ternary complex were obtained readily in crystallization screens. RESULTS |
|
12 26 Fab/IL-17A/HAP complex_assembly Crystals of Fab/IL-17A/HAP ternary complex were obtained readily in crystallization screens. RESULTS |
|
68 91 crystallization screens experimental_method Crystals of Fab/IL-17A/HAP ternary complex were obtained readily in crystallization screens. RESULTS |
|
0 15 Crystallization experimental_method Crystallization of IL-17A and its binding partners was accomplished using two forms of IL-17A. RESULTS |
|
19 25 IL-17A protein Crystallization of IL-17A and its binding partners was accomplished using two forms of IL-17A. RESULTS |
|
87 93 IL-17A protein Crystallization of IL-17A and its binding partners was accomplished using two forms of IL-17A. RESULTS |
|
64 70 IL-17A protein These were, respectively, a presumably more homogeneous form of IL-17A that lacked the disordered N-terminal peptide and a full-length form of the cytokine with a full complement of disulfide bonds. RESULTS |
|
76 82 lacked protein_state These were, respectively, a presumably more homogeneous form of IL-17A that lacked the disordered N-terminal peptide and a full-length form of the cytokine with a full complement of disulfide bonds. RESULTS |
|
87 97 disordered protein_state These were, respectively, a presumably more homogeneous form of IL-17A that lacked the disordered N-terminal peptide and a full-length form of the cytokine with a full complement of disulfide bonds. RESULTS |
|
98 116 N-terminal peptide structure_element These were, respectively, a presumably more homogeneous form of IL-17A that lacked the disordered N-terminal peptide and a full-length form of the cytokine with a full complement of disulfide bonds. RESULTS |
|
123 134 full-length protein_state These were, respectively, a presumably more homogeneous form of IL-17A that lacked the disordered N-terminal peptide and a full-length form of the cytokine with a full complement of disulfide bonds. RESULTS |
|
147 155 cytokine protein_type These were, respectively, a presumably more homogeneous form of IL-17A that lacked the disordered N-terminal peptide and a full-length form of the cytokine with a full complement of disulfide bonds. RESULTS |
|
182 197 disulfide bonds ptm These were, respectively, a presumably more homogeneous form of IL-17A that lacked the disordered N-terminal peptide and a full-length form of the cytokine with a full complement of disulfide bonds. RESULTS |
|
0 8 Crystals evidence Crystals of the Fab/truncated IL-17A/HAP complex diffracted to 2.2 Å, and the Fab/full length IL-17A/HAP complex diffracted to 3.0 Å (Supplementary Table S3). RESULTS |
|
16 40 Fab/truncated IL-17A/HAP complex_assembly Crystals of the Fab/truncated IL-17A/HAP complex diffracted to 2.2 Å, and the Fab/full length IL-17A/HAP complex diffracted to 3.0 Å (Supplementary Table S3). RESULTS |
|
78 104 Fab/full length IL-17A/HAP complex_assembly Crystals of the Fab/truncated IL-17A/HAP complex diffracted to 2.2 Å, and the Fab/full length IL-17A/HAP complex diffracted to 3.0 Å (Supplementary Table S3). RESULTS |
|
5 15 structures evidence Both structures were solved by molecular replacement. RESULTS |
|
31 52 molecular replacement experimental_method Both structures were solved by molecular replacement. RESULTS |
|
15 27 crystallized experimental_method Both complexes crystallized in the space group of P321, with half the complex (1 Fab/1 IL-17A monomer/1 HAP) in the asymmetric unit. RESULTS |
|
81 84 Fab structure_element Both complexes crystallized in the space group of P321, with half the complex (1 Fab/1 IL-17A monomer/1 HAP) in the asymmetric unit. RESULTS |
|
87 93 IL-17A protein Both complexes crystallized in the space group of P321, with half the complex (1 Fab/1 IL-17A monomer/1 HAP) in the asymmetric unit. RESULTS |
|
94 101 monomer oligomeric_state Both complexes crystallized in the space group of P321, with half the complex (1 Fab/1 IL-17A monomer/1 HAP) in the asymmetric unit. RESULTS |
|
104 107 HAP chemical Both complexes crystallized in the space group of P321, with half the complex (1 Fab/1 IL-17A monomer/1 HAP) in the asymmetric unit. RESULTS |
|
4 10 intact protein_state The intact complex can be generated by applying crystallographic 2-fold symmetry. RESULTS |
|
0 18 Electron densities evidence Electron densities for HAP residues Ile1-Asn14 were readily interpretable with the exception of Lys15, which is disordered. RESULTS |
|
23 26 HAP chemical Electron densities for HAP residues Ile1-Asn14 were readily interpretable with the exception of Lys15, which is disordered. RESULTS |
|
36 46 Ile1-Asn14 residue_range Electron densities for HAP residues Ile1-Asn14 were readily interpretable with the exception of Lys15, which is disordered. RESULTS |
|
96 101 Lys15 residue_name_number Electron densities for HAP residues Ile1-Asn14 were readily interpretable with the exception of Lys15, which is disordered. RESULTS |
|
112 122 disordered protein_state Electron densities for HAP residues Ile1-Asn14 were readily interpretable with the exception of Lys15, which is disordered. RESULTS |
|
34 51 complex structure evidence When considering the protein, the complex structure containing the full length IL-17A is identical to that of the truncated IL-17A, with the exception of Cys106 (Ser106 in the truncated IL-17A), which is disordered. RESULTS |
|
67 78 full length protein_state When considering the protein, the complex structure containing the full length IL-17A is identical to that of the truncated IL-17A, with the exception of Cys106 (Ser106 in the truncated IL-17A), which is disordered. RESULTS |
|
79 85 IL-17A protein When considering the protein, the complex structure containing the full length IL-17A is identical to that of the truncated IL-17A, with the exception of Cys106 (Ser106 in the truncated IL-17A), which is disordered. RESULTS |
|
114 123 truncated protein_state When considering the protein, the complex structure containing the full length IL-17A is identical to that of the truncated IL-17A, with the exception of Cys106 (Ser106 in the truncated IL-17A), which is disordered. RESULTS |
|
124 130 IL-17A protein When considering the protein, the complex structure containing the full length IL-17A is identical to that of the truncated IL-17A, with the exception of Cys106 (Ser106 in the truncated IL-17A), which is disordered. RESULTS |
|
154 160 Cys106 residue_name_number When considering the protein, the complex structure containing the full length IL-17A is identical to that of the truncated IL-17A, with the exception of Cys106 (Ser106 in the truncated IL-17A), which is disordered. RESULTS |
|
162 168 Ser106 residue_name_number When considering the protein, the complex structure containing the full length IL-17A is identical to that of the truncated IL-17A, with the exception of Cys106 (Ser106 in the truncated IL-17A), which is disordered. RESULTS |
|
176 185 truncated protein_state When considering the protein, the complex structure containing the full length IL-17A is identical to that of the truncated IL-17A, with the exception of Cys106 (Ser106 in the truncated IL-17A), which is disordered. RESULTS |
|
186 192 IL-17A protein When considering the protein, the complex structure containing the full length IL-17A is identical to that of the truncated IL-17A, with the exception of Cys106 (Ser106 in the truncated IL-17A), which is disordered. RESULTS |
|
204 214 disordered protein_state When considering the protein, the complex structure containing the full length IL-17A is identical to that of the truncated IL-17A, with the exception of Cys106 (Ser106 in the truncated IL-17A), which is disordered. RESULTS |
|
0 6 Cys106 residue_name_number Cys106 is covalently linked to Cys10 that resides in the disordered N-terminal peptide in the full length IL-17A. RESULTS |
|
31 36 Cys10 residue_name_number Cys106 is covalently linked to Cys10 that resides in the disordered N-terminal peptide in the full length IL-17A. RESULTS |
|
57 67 disordered protein_state Cys106 is covalently linked to Cys10 that resides in the disordered N-terminal peptide in the full length IL-17A. RESULTS |
|
68 86 N-terminal peptide structure_element Cys106 is covalently linked to Cys10 that resides in the disordered N-terminal peptide in the full length IL-17A. RESULTS |
|
94 105 full length protein_state Cys106 is covalently linked to Cys10 that resides in the disordered N-terminal peptide in the full length IL-17A. RESULTS |
|
106 112 IL-17A protein Cys106 is covalently linked to Cys10 that resides in the disordered N-terminal peptide in the full length IL-17A. RESULTS |
|
8 17 structure evidence Overall structure of Fab/IL-17A/HAP complex RESULTS |
|
21 35 Fab/IL-17A/HAP complex_assembly Overall structure of Fab/IL-17A/HAP complex RESULTS |
|
37 46 structure evidence In a similar manner to the published structure of Fab/IL-17A complex, two Fab molecules bind symmetrically to the C-terminal of the cytokine dimer, interacting with epitopes from both monomers (Fig. 2A). RESULTS |
|
50 60 Fab/IL-17A complex_assembly In a similar manner to the published structure of Fab/IL-17A complex, two Fab molecules bind symmetrically to the C-terminal of the cytokine dimer, interacting with epitopes from both monomers (Fig. 2A). RESULTS |
|
74 77 Fab structure_element In a similar manner to the published structure of Fab/IL-17A complex, two Fab molecules bind symmetrically to the C-terminal of the cytokine dimer, interacting with epitopes from both monomers (Fig. 2A). RESULTS |
|
132 140 cytokine protein_type In a similar manner to the published structure of Fab/IL-17A complex, two Fab molecules bind symmetrically to the C-terminal of the cytokine dimer, interacting with epitopes from both monomers (Fig. 2A). RESULTS |
|
141 146 dimer oligomeric_state In a similar manner to the published structure of Fab/IL-17A complex, two Fab molecules bind symmetrically to the C-terminal of the cytokine dimer, interacting with epitopes from both monomers (Fig. 2A). RESULTS |
|
184 192 monomers oligomeric_state In a similar manner to the published structure of Fab/IL-17A complex, two Fab molecules bind symmetrically to the C-terminal of the cytokine dimer, interacting with epitopes from both monomers (Fig. 2A). RESULTS |
|
14 17 HAP chemical Two copies of HAP bind to the N-terminal of the cytokine dimer, also symmetrically, and each HAP molecule also interacts with both IL-17A monomers (Fig. 2). RESULTS |
|
48 56 cytokine protein_type Two copies of HAP bind to the N-terminal of the cytokine dimer, also symmetrically, and each HAP molecule also interacts with both IL-17A monomers (Fig. 2). RESULTS |
|
57 62 dimer oligomeric_state Two copies of HAP bind to the N-terminal of the cytokine dimer, also symmetrically, and each HAP molecule also interacts with both IL-17A monomers (Fig. 2). RESULTS |
|
93 96 HAP chemical Two copies of HAP bind to the N-terminal of the cytokine dimer, also symmetrically, and each HAP molecule also interacts with both IL-17A monomers (Fig. 2). RESULTS |
|
131 137 IL-17A protein Two copies of HAP bind to the N-terminal of the cytokine dimer, also symmetrically, and each HAP molecule also interacts with both IL-17A monomers (Fig. 2). RESULTS |
|
138 146 monomers oligomeric_state Two copies of HAP bind to the N-terminal of the cytokine dimer, also symmetrically, and each HAP molecule also interacts with both IL-17A monomers (Fig. 2). RESULTS |
|
31 42 Secukinumab chemical Based on disclosed epitopes of Secukinumab and Ixekizumab, HAP binds to IL-17A at an area that is also different from those of those two antibodies. RESULTS |
|
47 57 Ixekizumab chemical Based on disclosed epitopes of Secukinumab and Ixekizumab, HAP binds to IL-17A at an area that is also different from those of those two antibodies. RESULTS |
|
59 62 HAP chemical Based on disclosed epitopes of Secukinumab and Ixekizumab, HAP binds to IL-17A at an area that is also different from those of those two antibodies. RESULTS |
|
72 78 IL-17A protein Based on disclosed epitopes of Secukinumab and Ixekizumab, HAP binds to IL-17A at an area that is also different from those of those two antibodies. RESULTS |
|
137 147 antibodies protein_type Based on disclosed epitopes of Secukinumab and Ixekizumab, HAP binds to IL-17A at an area that is also different from those of those two antibodies. RESULTS |
|
15 25 5 residues residue_range The N-terminal 5 residues of HAP, 1IHVTI, form an amphipathic β-strand that inserts between β-strand 4 of one IL-17A monomer and β-strand 0 (the first ordered peptide of IL-17A) of the second monomer. RESULTS |
|
29 32 HAP chemical The N-terminal 5 residues of HAP, 1IHVTI, form an amphipathic β-strand that inserts between β-strand 4 of one IL-17A monomer and β-strand 0 (the first ordered peptide of IL-17A) of the second monomer. RESULTS |
|
34 40 1IHVTI chemical The N-terminal 5 residues of HAP, 1IHVTI, form an amphipathic β-strand that inserts between β-strand 4 of one IL-17A monomer and β-strand 0 (the first ordered peptide of IL-17A) of the second monomer. RESULTS |
|
50 61 amphipathic protein_state The N-terminal 5 residues of HAP, 1IHVTI, form an amphipathic β-strand that inserts between β-strand 4 of one IL-17A monomer and β-strand 0 (the first ordered peptide of IL-17A) of the second monomer. RESULTS |
|
62 70 β-strand structure_element The N-terminal 5 residues of HAP, 1IHVTI, form an amphipathic β-strand that inserts between β-strand 4 of one IL-17A monomer and β-strand 0 (the first ordered peptide of IL-17A) of the second monomer. RESULTS |
|
92 102 β-strand 4 structure_element The N-terminal 5 residues of HAP, 1IHVTI, form an amphipathic β-strand that inserts between β-strand 4 of one IL-17A monomer and β-strand 0 (the first ordered peptide of IL-17A) of the second monomer. RESULTS |
|
110 116 IL-17A protein The N-terminal 5 residues of HAP, 1IHVTI, form an amphipathic β-strand that inserts between β-strand 4 of one IL-17A monomer and β-strand 0 (the first ordered peptide of IL-17A) of the second monomer. RESULTS |
|
117 124 monomer oligomeric_state The N-terminal 5 residues of HAP, 1IHVTI, form an amphipathic β-strand that inserts between β-strand 4 of one IL-17A monomer and β-strand 0 (the first ordered peptide of IL-17A) of the second monomer. RESULTS |
|
129 139 β-strand 0 structure_element The N-terminal 5 residues of HAP, 1IHVTI, form an amphipathic β-strand that inserts between β-strand 4 of one IL-17A monomer and β-strand 0 (the first ordered peptide of IL-17A) of the second monomer. RESULTS |
|
170 176 IL-17A protein The N-terminal 5 residues of HAP, 1IHVTI, form an amphipathic β-strand that inserts between β-strand 4 of one IL-17A monomer and β-strand 0 (the first ordered peptide of IL-17A) of the second monomer. RESULTS |
|
192 199 monomer oligomeric_state The N-terminal 5 residues of HAP, 1IHVTI, form an amphipathic β-strand that inserts between β-strand 4 of one IL-17A monomer and β-strand 0 (the first ordered peptide of IL-17A) of the second monomer. RESULTS |
|
5 13 β-strand structure_element This β-strand is parallel to both strands 0 and 4 (Fig. 3B). RESULTS |
|
34 49 strands 0 and 4 structure_element This β-strand is parallel to both strands 0 and 4 (Fig. 3B). RESULTS |
|
0 9 Strands 0 structure_element Strands 0 of two IL-17A monomer are antiparallel, as appeared in other IL-17A structures. RESULTS |
|
17 23 IL-17A protein Strands 0 of two IL-17A monomer are antiparallel, as appeared in other IL-17A structures. RESULTS |
|
24 31 monomer oligomeric_state Strands 0 of two IL-17A monomer are antiparallel, as appeared in other IL-17A structures. RESULTS |
|
71 77 IL-17A protein Strands 0 of two IL-17A monomer are antiparallel, as appeared in other IL-17A structures. RESULTS |
|
78 88 structures evidence Strands 0 of two IL-17A monomer are antiparallel, as appeared in other IL-17A structures. RESULTS |
|
15 25 8 residues residue_range The C-terminal 8 residues of the HAP that are ordered in the structure, 7ADLWDWIN, form an amphipathic α-helix interacting with the second IL-17A monomer. RESULTS |
|
33 36 HAP chemical The C-terminal 8 residues of the HAP that are ordered in the structure, 7ADLWDWIN, form an amphipathic α-helix interacting with the second IL-17A monomer. RESULTS |
|
61 70 structure evidence The C-terminal 8 residues of the HAP that are ordered in the structure, 7ADLWDWIN, form an amphipathic α-helix interacting with the second IL-17A monomer. RESULTS |
|
72 81 7ADLWDWIN chemical The C-terminal 8 residues of the HAP that are ordered in the structure, 7ADLWDWIN, form an amphipathic α-helix interacting with the second IL-17A monomer. RESULTS |
|
91 102 amphipathic protein_state The C-terminal 8 residues of the HAP that are ordered in the structure, 7ADLWDWIN, form an amphipathic α-helix interacting with the second IL-17A monomer. RESULTS |
|
103 110 α-helix structure_element The C-terminal 8 residues of the HAP that are ordered in the structure, 7ADLWDWIN, form an amphipathic α-helix interacting with the second IL-17A monomer. RESULTS |
|
139 145 IL-17A protein The C-terminal 8 residues of the HAP that are ordered in the structure, 7ADLWDWIN, form an amphipathic α-helix interacting with the second IL-17A monomer. RESULTS |
|
146 153 monomer oligomeric_state The C-terminal 8 residues of the HAP that are ordered in the structure, 7ADLWDWIN, form an amphipathic α-helix interacting with the second IL-17A monomer. RESULTS |
|
0 4 Pro6 residue_name_number Pro6 of HAP makes a transition between the N-terminal β-strand and the C-terminal α-helix of HAP. RESULTS |
|
8 11 HAP chemical Pro6 of HAP makes a transition between the N-terminal β-strand and the C-terminal α-helix of HAP. RESULTS |
|
54 62 β-strand structure_element Pro6 of HAP makes a transition between the N-terminal β-strand and the C-terminal α-helix of HAP. RESULTS |
|
82 89 α-helix structure_element Pro6 of HAP makes a transition between the N-terminal β-strand and the C-terminal α-helix of HAP. RESULTS |
|
93 96 HAP chemical Pro6 of HAP makes a transition between the N-terminal β-strand and the C-terminal α-helix of HAP. RESULTS |
|
20 34 IL-17A/IL-17RA complex_assembly As a comparison, an IL-17A/IL-17RA complex structure (PDB code 4HSA) is also shown with IL-17A in the same orientation (Fig. 2C). RESULTS |
|
35 52 complex structure evidence As a comparison, an IL-17A/IL-17RA complex structure (PDB code 4HSA) is also shown with IL-17A in the same orientation (Fig. 2C). RESULTS |
|
88 94 IL-17A protein As a comparison, an IL-17A/IL-17RA complex structure (PDB code 4HSA) is also shown with IL-17A in the same orientation (Fig. 2C). RESULTS |
|
24 30 IL-17A protein Inhibition mechanism of IL-17A signaling by HAP RESULTS |
|
44 47 HAP chemical Inhibition mechanism of IL-17A signaling by HAP RESULTS |
|
0 7 IL-17RA protein IL-17RA binds IL-17A at three regions on the IL-17A homodimer. RESULTS |
|
14 20 IL-17A protein IL-17RA binds IL-17A at three regions on the IL-17A homodimer. RESULTS |
|
45 51 IL-17A protein IL-17RA binds IL-17A at three regions on the IL-17A homodimer. RESULTS |
|
52 61 homodimer oligomeric_state IL-17RA binds IL-17A at three regions on the IL-17A homodimer. RESULTS |
|
0 3 HAP chemical HAP binds IL-17A at region I. Region I is formed by residues at the ends of β strands 0 and 4, and from loops 1–2 and 3–4 of IL-17A (Fig. 2). RESULTS |
|
10 16 IL-17A protein HAP binds IL-17A at region I. Region I is formed by residues at the ends of β strands 0 and 4, and from loops 1–2 and 3–4 of IL-17A (Fig. 2). RESULTS |
|
20 28 region I structure_element HAP binds IL-17A at region I. Region I is formed by residues at the ends of β strands 0 and 4, and from loops 1–2 and 3–4 of IL-17A (Fig. 2). RESULTS |
|
30 38 Region I structure_element HAP binds IL-17A at region I. Region I is formed by residues at the ends of β strands 0 and 4, and from loops 1–2 and 3–4 of IL-17A (Fig. 2). RESULTS |
|
76 93 β strands 0 and 4 structure_element HAP binds IL-17A at region I. Region I is formed by residues at the ends of β strands 0 and 4, and from loops 1–2 and 3–4 of IL-17A (Fig. 2). RESULTS |
|
104 113 loops 1–2 structure_element HAP binds IL-17A at region I. Region I is formed by residues at the ends of β strands 0 and 4, and from loops 1–2 and 3–4 of IL-17A (Fig. 2). RESULTS |
|
118 121 3–4 structure_element HAP binds IL-17A at region I. Region I is formed by residues at the ends of β strands 0 and 4, and from loops 1–2 and 3–4 of IL-17A (Fig. 2). RESULTS |
|
125 131 IL-17A protein HAP binds IL-17A at region I. Region I is formed by residues at the ends of β strands 0 and 4, and from loops 1–2 and 3–4 of IL-17A (Fig. 2). RESULTS |
|
26 34 region I structure_element Conformational changes in region I induced by HAP binding alone may allosterically affect IL-17RA binding, but more importantly, the α-helix of HAP directly competes with IL-17RA for binding to IL-17A (Fig. 3). RESULTS |
|
46 49 HAP chemical Conformational changes in region I induced by HAP binding alone may allosterically affect IL-17RA binding, but more importantly, the α-helix of HAP directly competes with IL-17RA for binding to IL-17A (Fig. 3). RESULTS |
|
90 97 IL-17RA protein Conformational changes in region I induced by HAP binding alone may allosterically affect IL-17RA binding, but more importantly, the α-helix of HAP directly competes with IL-17RA for binding to IL-17A (Fig. 3). RESULTS |
|
133 140 α-helix structure_element Conformational changes in region I induced by HAP binding alone may allosterically affect IL-17RA binding, but more importantly, the α-helix of HAP directly competes with IL-17RA for binding to IL-17A (Fig. 3). RESULTS |
|
144 147 HAP chemical Conformational changes in region I induced by HAP binding alone may allosterically affect IL-17RA binding, but more importantly, the α-helix of HAP directly competes with IL-17RA for binding to IL-17A (Fig. 3). RESULTS |
|
171 178 IL-17RA protein Conformational changes in region I induced by HAP binding alone may allosterically affect IL-17RA binding, but more importantly, the α-helix of HAP directly competes with IL-17RA for binding to IL-17A (Fig. 3). RESULTS |
|
194 200 IL-17A protein Conformational changes in region I induced by HAP binding alone may allosterically affect IL-17RA binding, but more importantly, the α-helix of HAP directly competes with IL-17RA for binding to IL-17A (Fig. 3). RESULTS |
|
46 53 α helix structure_element The most significant interactions between the α helix of HAP and IL-17A involve Trp12 of HAP, which binds in a hydrophobic pocket in IL-17A formed by the side chains of Phe110, Tyr62, Pro59 and the hydrophobic portion of the Arg101 side chain (Fig. 3A). RESULTS |
|
57 60 HAP chemical The most significant interactions between the α helix of HAP and IL-17A involve Trp12 of HAP, which binds in a hydrophobic pocket in IL-17A formed by the side chains of Phe110, Tyr62, Pro59 and the hydrophobic portion of the Arg101 side chain (Fig. 3A). RESULTS |
|
65 71 IL-17A protein The most significant interactions between the α helix of HAP and IL-17A involve Trp12 of HAP, which binds in a hydrophobic pocket in IL-17A formed by the side chains of Phe110, Tyr62, Pro59 and the hydrophobic portion of the Arg101 side chain (Fig. 3A). RESULTS |
|
80 85 Trp12 residue_name_number The most significant interactions between the α helix of HAP and IL-17A involve Trp12 of HAP, which binds in a hydrophobic pocket in IL-17A formed by the side chains of Phe110, Tyr62, Pro59 and the hydrophobic portion of the Arg101 side chain (Fig. 3A). RESULTS |
|
89 92 HAP chemical The most significant interactions between the α helix of HAP and IL-17A involve Trp12 of HAP, which binds in a hydrophobic pocket in IL-17A formed by the side chains of Phe110, Tyr62, Pro59 and the hydrophobic portion of the Arg101 side chain (Fig. 3A). RESULTS |
|
111 129 hydrophobic pocket site The most significant interactions between the α helix of HAP and IL-17A involve Trp12 of HAP, which binds in a hydrophobic pocket in IL-17A formed by the side chains of Phe110, Tyr62, Pro59 and the hydrophobic portion of the Arg101 side chain (Fig. 3A). RESULTS |
|
133 139 IL-17A protein The most significant interactions between the α helix of HAP and IL-17A involve Trp12 of HAP, which binds in a hydrophobic pocket in IL-17A formed by the side chains of Phe110, Tyr62, Pro59 and the hydrophobic portion of the Arg101 side chain (Fig. 3A). RESULTS |
|
169 175 Phe110 residue_name_number The most significant interactions between the α helix of HAP and IL-17A involve Trp12 of HAP, which binds in a hydrophobic pocket in IL-17A formed by the side chains of Phe110, Tyr62, Pro59 and the hydrophobic portion of the Arg101 side chain (Fig. 3A). RESULTS |
|
177 182 Tyr62 residue_name_number The most significant interactions between the α helix of HAP and IL-17A involve Trp12 of HAP, which binds in a hydrophobic pocket in IL-17A formed by the side chains of Phe110, Tyr62, Pro59 and the hydrophobic portion of the Arg101 side chain (Fig. 3A). RESULTS |
|
184 189 Pro59 residue_name_number The most significant interactions between the α helix of HAP and IL-17A involve Trp12 of HAP, which binds in a hydrophobic pocket in IL-17A formed by the side chains of Phe110, Tyr62, Pro59 and the hydrophobic portion of the Arg101 side chain (Fig. 3A). RESULTS |
|
225 231 Arg101 residue_name_number The most significant interactions between the α helix of HAP and IL-17A involve Trp12 of HAP, which binds in a hydrophobic pocket in IL-17A formed by the side chains of Phe110, Tyr62, Pro59 and the hydrophobic portion of the Arg101 side chain (Fig. 3A). RESULTS |
|
4 9 Trp12 residue_name_number The Trp12 side chain of HAP donates a hydrogen bond to the main chain oxygen of Pro69 of IL-17A. RESULTS |
|
24 27 HAP chemical The Trp12 side chain of HAP donates a hydrogen bond to the main chain oxygen of Pro69 of IL-17A. RESULTS |
|
38 51 hydrogen bond bond_interaction The Trp12 side chain of HAP donates a hydrogen bond to the main chain oxygen of Pro69 of IL-17A. RESULTS |
|
80 85 Pro69 residue_name_number The Trp12 side chain of HAP donates a hydrogen bond to the main chain oxygen of Pro69 of IL-17A. RESULTS |
|
89 95 IL-17A protein The Trp12 side chain of HAP donates a hydrogen bond to the main chain oxygen of Pro69 of IL-17A. RESULTS |
|
23 29 Arg101 residue_name_number The positively charged Arg101 side chain of the IL-17A engages in a charge-helix dipole interaction with the main chain oxygen of Trp12. RESULTS |
|
48 54 IL-17A protein The positively charged Arg101 side chain of the IL-17A engages in a charge-helix dipole interaction with the main chain oxygen of Trp12. RESULTS |
|
68 99 charge-helix dipole interaction bond_interaction The positively charged Arg101 side chain of the IL-17A engages in a charge-helix dipole interaction with the main chain oxygen of Trp12. RESULTS |
|
130 135 Trp12 residue_name_number The positively charged Arg101 side chain of the IL-17A engages in a charge-helix dipole interaction with the main chain oxygen of Trp12. RESULTS |
|
14 18 Leu9 residue_name_number Additionally, Leu9 and Ile13 of the HAP have hydrophobic interactions with IL-17A, and the Asp8 side chain has hydrogen bond and ion pair interactions with Tyr62 and Lys114 of IL-17A, respectively. RESULTS |
|
23 28 Ile13 residue_name_number Additionally, Leu9 and Ile13 of the HAP have hydrophobic interactions with IL-17A, and the Asp8 side chain has hydrogen bond and ion pair interactions with Tyr62 and Lys114 of IL-17A, respectively. RESULTS |
|
36 39 HAP chemical Additionally, Leu9 and Ile13 of the HAP have hydrophobic interactions with IL-17A, and the Asp8 side chain has hydrogen bond and ion pair interactions with Tyr62 and Lys114 of IL-17A, respectively. RESULTS |
|
45 69 hydrophobic interactions bond_interaction Additionally, Leu9 and Ile13 of the HAP have hydrophobic interactions with IL-17A, and the Asp8 side chain has hydrogen bond and ion pair interactions with Tyr62 and Lys114 of IL-17A, respectively. RESULTS |
|
75 81 IL-17A protein Additionally, Leu9 and Ile13 of the HAP have hydrophobic interactions with IL-17A, and the Asp8 side chain has hydrogen bond and ion pair interactions with Tyr62 and Lys114 of IL-17A, respectively. RESULTS |
|
91 95 Asp8 residue_name_number Additionally, Leu9 and Ile13 of the HAP have hydrophobic interactions with IL-17A, and the Asp8 side chain has hydrogen bond and ion pair interactions with Tyr62 and Lys114 of IL-17A, respectively. RESULTS |
|
111 124 hydrogen bond bond_interaction Additionally, Leu9 and Ile13 of the HAP have hydrophobic interactions with IL-17A, and the Asp8 side chain has hydrogen bond and ion pair interactions with Tyr62 and Lys114 of IL-17A, respectively. RESULTS |
|
129 150 ion pair interactions bond_interaction Additionally, Leu9 and Ile13 of the HAP have hydrophobic interactions with IL-17A, and the Asp8 side chain has hydrogen bond and ion pair interactions with Tyr62 and Lys114 of IL-17A, respectively. RESULTS |
|
156 161 Tyr62 residue_name_number Additionally, Leu9 and Ile13 of the HAP have hydrophobic interactions with IL-17A, and the Asp8 side chain has hydrogen bond and ion pair interactions with Tyr62 and Lys114 of IL-17A, respectively. RESULTS |
|
166 172 Lys114 residue_name_number Additionally, Leu9 and Ile13 of the HAP have hydrophobic interactions with IL-17A, and the Asp8 side chain has hydrogen bond and ion pair interactions with Tyr62 and Lys114 of IL-17A, respectively. RESULTS |
|
176 182 IL-17A protein Additionally, Leu9 and Ile13 of the HAP have hydrophobic interactions with IL-17A, and the Asp8 side chain has hydrogen bond and ion pair interactions with Tyr62 and Lys114 of IL-17A, respectively. RESULTS |
|
3 11 region I structure_element In region I, an IL-17RA peptide interacts with IL-17A in a very similar fashion to the α-helix of HAP. RESULTS |
|
16 23 IL-17RA protein In region I, an IL-17RA peptide interacts with IL-17A in a very similar fashion to the α-helix of HAP. RESULTS |
|
47 53 IL-17A protein In region I, an IL-17RA peptide interacts with IL-17A in a very similar fashion to the α-helix of HAP. RESULTS |
|
87 94 α-helix structure_element In region I, an IL-17RA peptide interacts with IL-17A in a very similar fashion to the α-helix of HAP. RESULTS |
|
98 101 HAP chemical In region I, an IL-17RA peptide interacts with IL-17A in a very similar fashion to the α-helix of HAP. RESULTS |
|
4 11 IL-17RA protein The IL-17RA peptide has sequences of 27LDDSWI, and part of the peptide is also α-helical (Fig. 3B). RESULTS |
|
37 45 27LDDSWI chemical The IL-17RA peptide has sequences of 27LDDSWI, and part of the peptide is also α-helical (Fig. 3B). RESULTS |
|
79 88 α-helical structure_element The IL-17RA peptide has sequences of 27LDDSWI, and part of the peptide is also α-helical (Fig. 3B). RESULTS |
|
0 4 Leu7 residue_name_number Leu7, Trp31 and Ile32 of IL-17RA interact very similarly with the same residues of IL-17A as Leu9, Trp12 and Ile13 of HAP (Fig. 3B). RESULTS |
|
6 11 Trp31 residue_name_number Leu7, Trp31 and Ile32 of IL-17RA interact very similarly with the same residues of IL-17A as Leu9, Trp12 and Ile13 of HAP (Fig. 3B). RESULTS |
|
16 21 Ile32 residue_name_number Leu7, Trp31 and Ile32 of IL-17RA interact very similarly with the same residues of IL-17A as Leu9, Trp12 and Ile13 of HAP (Fig. 3B). RESULTS |
|
25 32 IL-17RA protein Leu7, Trp31 and Ile32 of IL-17RA interact very similarly with the same residues of IL-17A as Leu9, Trp12 and Ile13 of HAP (Fig. 3B). RESULTS |
|
83 89 IL-17A protein Leu7, Trp31 and Ile32 of IL-17RA interact very similarly with the same residues of IL-17A as Leu9, Trp12 and Ile13 of HAP (Fig. 3B). RESULTS |
|
93 97 Leu9 residue_name_number Leu7, Trp31 and Ile32 of IL-17RA interact very similarly with the same residues of IL-17A as Leu9, Trp12 and Ile13 of HAP (Fig. 3B). RESULTS |
|
99 104 Trp12 residue_name_number Leu7, Trp31 and Ile32 of IL-17RA interact very similarly with the same residues of IL-17A as Leu9, Trp12 and Ile13 of HAP (Fig. 3B). RESULTS |
|
109 114 Ile13 residue_name_number Leu7, Trp31 and Ile32 of IL-17RA interact very similarly with the same residues of IL-17A as Leu9, Trp12 and Ile13 of HAP (Fig. 3B). RESULTS |
|
118 121 HAP chemical Leu7, Trp31 and Ile32 of IL-17RA interact very similarly with the same residues of IL-17A as Leu9, Trp12 and Ile13 of HAP (Fig. 3B). RESULTS |
|
19 26 α-helix structure_element In this sense, the α-helix of HAP with a sequence of 9LWDWI is a good mimetic of the 27LDDSWI peptide of IL-17RA. RESULTS |
|
30 33 HAP chemical In this sense, the α-helix of HAP with a sequence of 9LWDWI is a good mimetic of the 27LDDSWI peptide of IL-17RA. RESULTS |
|
53 59 9LWDWI chemical In this sense, the α-helix of HAP with a sequence of 9LWDWI is a good mimetic of the 27LDDSWI peptide of IL-17RA. RESULTS |
|
85 93 27LDDSWI chemical In this sense, the α-helix of HAP with a sequence of 9LWDWI is a good mimetic of the 27LDDSWI peptide of IL-17RA. RESULTS |
|
105 112 IL-17RA protein In this sense, the α-helix of HAP with a sequence of 9LWDWI is a good mimetic of the 27LDDSWI peptide of IL-17RA. RESULTS |
|
4 12 β-strand structure_element The β-strand of HAP has no equivalent in IL-17RA. RESULTS |
|
16 19 HAP chemical The β-strand of HAP has no equivalent in IL-17RA. RESULTS |
|
41 48 IL-17RA protein The β-strand of HAP has no equivalent in IL-17RA. RESULTS |
|
23 33 β-strand 0 structure_element However, it mimics the β-strand 0 of IL-17A. RESULTS |
|
37 43 IL-17A protein However, it mimics the β-strand 0 of IL-17A. RESULTS |
|
4 15 amphipathic protein_state The amphipathic β-strand of HAP orients the hydrophilic side chains of His2 and Thr4 outwards, and the hydrophobic side chains of Ile1, Val3 and Ile5 inward (Fig. 3A). RESULTS |
|
16 24 β-strand structure_element The amphipathic β-strand of HAP orients the hydrophilic side chains of His2 and Thr4 outwards, and the hydrophobic side chains of Ile1, Val3 and Ile5 inward (Fig. 3A). RESULTS |
|
28 31 HAP chemical The amphipathic β-strand of HAP orients the hydrophilic side chains of His2 and Thr4 outwards, and the hydrophobic side chains of Ile1, Val3 and Ile5 inward (Fig. 3A). RESULTS |
|
71 75 His2 residue_name_number The amphipathic β-strand of HAP orients the hydrophilic side chains of His2 and Thr4 outwards, and the hydrophobic side chains of Ile1, Val3 and Ile5 inward (Fig. 3A). RESULTS |
|
80 84 Thr4 residue_name_number The amphipathic β-strand of HAP orients the hydrophilic side chains of His2 and Thr4 outwards, and the hydrophobic side chains of Ile1, Val3 and Ile5 inward (Fig. 3A). RESULTS |
|
130 134 Ile1 residue_name_number The amphipathic β-strand of HAP orients the hydrophilic side chains of His2 and Thr4 outwards, and the hydrophobic side chains of Ile1, Val3 and Ile5 inward (Fig. 3A). RESULTS |
|
136 140 Val3 residue_name_number The amphipathic β-strand of HAP orients the hydrophilic side chains of His2 and Thr4 outwards, and the hydrophobic side chains of Ile1, Val3 and Ile5 inward (Fig. 3A). RESULTS |
|
145 149 Ile5 residue_name_number The amphipathic β-strand of HAP orients the hydrophilic side chains of His2 and Thr4 outwards, and the hydrophobic side chains of Ile1, Val3 and Ile5 inward (Fig. 3A). RESULTS |
|
0 10 β-strand 0 structure_element β-strand 0 in IL-17A is also amphipathic with the sequence of 21TVMVNLNI. RESULTS |
|
14 20 IL-17A protein β-strand 0 in IL-17A is also amphipathic with the sequence of 21TVMVNLNI. RESULTS |
|
29 40 amphipathic protein_state β-strand 0 in IL-17A is also amphipathic with the sequence of 21TVMVNLNI. RESULTS |
|
62 72 21TVMVNLNI chemical β-strand 0 in IL-17A is also amphipathic with the sequence of 21TVMVNLNI. RESULTS |
|
7 13 IL-17A protein In all IL-17A structures obtained to date, β-strand 0 orients the hydrophilic side chains of Thr21, Asn25 and Asn27 outward, and the hydrophobic side chains of Val22, Val24, Leu26 and Ile28 inward. RESULTS |
|
14 24 structures evidence In all IL-17A structures obtained to date, β-strand 0 orients the hydrophilic side chains of Thr21, Asn25 and Asn27 outward, and the hydrophobic side chains of Val22, Val24, Leu26 and Ile28 inward. RESULTS |
|
43 53 β-strand 0 structure_element In all IL-17A structures obtained to date, β-strand 0 orients the hydrophilic side chains of Thr21, Asn25 and Asn27 outward, and the hydrophobic side chains of Val22, Val24, Leu26 and Ile28 inward. RESULTS |
|
93 98 Thr21 residue_name_number In all IL-17A structures obtained to date, β-strand 0 orients the hydrophilic side chains of Thr21, Asn25 and Asn27 outward, and the hydrophobic side chains of Val22, Val24, Leu26 and Ile28 inward. RESULTS |
|
100 105 Asn25 residue_name_number In all IL-17A structures obtained to date, β-strand 0 orients the hydrophilic side chains of Thr21, Asn25 and Asn27 outward, and the hydrophobic side chains of Val22, Val24, Leu26 and Ile28 inward. RESULTS |
|
110 115 Asn27 residue_name_number In all IL-17A structures obtained to date, β-strand 0 orients the hydrophilic side chains of Thr21, Asn25 and Asn27 outward, and the hydrophobic side chains of Val22, Val24, Leu26 and Ile28 inward. RESULTS |
|
160 165 Val22 residue_name_number In all IL-17A structures obtained to date, β-strand 0 orients the hydrophilic side chains of Thr21, Asn25 and Asn27 outward, and the hydrophobic side chains of Val22, Val24, Leu26 and Ile28 inward. RESULTS |
|
167 172 Val24 residue_name_number In all IL-17A structures obtained to date, β-strand 0 orients the hydrophilic side chains of Thr21, Asn25 and Asn27 outward, and the hydrophobic side chains of Val22, Val24, Leu26 and Ile28 inward. RESULTS |
|
174 179 Leu26 residue_name_number In all IL-17A structures obtained to date, β-strand 0 orients the hydrophilic side chains of Thr21, Asn25 and Asn27 outward, and the hydrophobic side chains of Val22, Val24, Leu26 and Ile28 inward. RESULTS |
|
184 189 Ile28 residue_name_number In all IL-17A structures obtained to date, β-strand 0 orients the hydrophilic side chains of Thr21, Asn25 and Asn27 outward, and the hydrophobic side chains of Val22, Val24, Leu26 and Ile28 inward. RESULTS |
|
4 18 binding pocket site The binding pocket occupied by either Trp12 of HAP or Trp31 of IL-17RA is not formed in the apo IL-17A structure (Fig. 3C). RESULTS |
|
38 43 Trp12 residue_name_number The binding pocket occupied by either Trp12 of HAP or Trp31 of IL-17RA is not formed in the apo IL-17A structure (Fig. 3C). RESULTS |
|
47 50 HAP chemical The binding pocket occupied by either Trp12 of HAP or Trp31 of IL-17RA is not formed in the apo IL-17A structure (Fig. 3C). RESULTS |
|
54 59 Trp31 residue_name_number The binding pocket occupied by either Trp12 of HAP or Trp31 of IL-17RA is not formed in the apo IL-17A structure (Fig. 3C). RESULTS |
|
63 70 IL-17RA protein The binding pocket occupied by either Trp12 of HAP or Trp31 of IL-17RA is not formed in the apo IL-17A structure (Fig. 3C). RESULTS |
|
92 95 apo protein_state The binding pocket occupied by either Trp12 of HAP or Trp31 of IL-17RA is not formed in the apo IL-17A structure (Fig. 3C). RESULTS |
|
96 102 IL-17A protein The binding pocket occupied by either Trp12 of HAP or Trp31 of IL-17RA is not formed in the apo IL-17A structure (Fig. 3C). RESULTS |
|
103 112 structure evidence The binding pocket occupied by either Trp12 of HAP or Trp31 of IL-17RA is not formed in the apo IL-17A structure (Fig. 3C). RESULTS |
|
26 32 IL-17A protein Conformational changes of IL-17A are needed for both HAP and IL-17RA to bind to that region. RESULTS |
|
53 56 HAP chemical Conformational changes of IL-17A are needed for both HAP and IL-17RA to bind to that region. RESULTS |
|
61 68 IL-17RA protein Conformational changes of IL-17A are needed for both HAP and IL-17RA to bind to that region. RESULTS |
|
17 20 HAP chemical Particularly for HAP, β-strands 0 have to shift out of the hydrophobic cleft formed by the main body of the IL-17A by as much as 10 Å between Cα atoms (Fig. 3C). RESULTS |
|
22 33 β-strands 0 structure_element Particularly for HAP, β-strands 0 have to shift out of the hydrophobic cleft formed by the main body of the IL-17A by as much as 10 Å between Cα atoms (Fig. 3C). RESULTS |
|
59 76 hydrophobic cleft site Particularly for HAP, β-strands 0 have to shift out of the hydrophobic cleft formed by the main body of the IL-17A by as much as 10 Å between Cα atoms (Fig. 3C). RESULTS |
|
91 100 main body structure_element Particularly for HAP, β-strands 0 have to shift out of the hydrophobic cleft formed by the main body of the IL-17A by as much as 10 Å between Cα atoms (Fig. 3C). RESULTS |
|
108 114 IL-17A protein Particularly for HAP, β-strands 0 have to shift out of the hydrophobic cleft formed by the main body of the IL-17A by as much as 10 Å between Cα atoms (Fig. 3C). RESULTS |
|
19 22 apo protein_state Disruptions of the apo IL-17A structure by HAP binding are apparently compensated for by formation of the new interactions that involve almost the entire HAP molecule (Fig. 3B). RESULTS |
|
23 29 IL-17A protein Disruptions of the apo IL-17A structure by HAP binding are apparently compensated for by formation of the new interactions that involve almost the entire HAP molecule (Fig. 3B). RESULTS |
|
30 39 structure evidence Disruptions of the apo IL-17A structure by HAP binding are apparently compensated for by formation of the new interactions that involve almost the entire HAP molecule (Fig. 3B). RESULTS |
|
43 46 HAP chemical Disruptions of the apo IL-17A structure by HAP binding are apparently compensated for by formation of the new interactions that involve almost the entire HAP molecule (Fig. 3B). RESULTS |
|
154 157 HAP chemical Disruptions of the apo IL-17A structure by HAP binding are apparently compensated for by formation of the new interactions that involve almost the entire HAP molecule (Fig. 3B). RESULTS |
|
33 36 SAR experimental_method Structure basis for the observed SAR of peptides RESULTS |
|
4 14 IL-17A/HAP complex_assembly The IL-17A/HAP complex structure obtained is very consistent with the observed SAR of our identified peptide inhibitors, explaining well how the evolution of the initial phage peptide 1 to HAP and 45 improved its potency (Supplementary Figure S7). RESULTS |
|
15 32 complex structure evidence The IL-17A/HAP complex structure obtained is very consistent with the observed SAR of our identified peptide inhibitors, explaining well how the evolution of the initial phage peptide 1 to HAP and 45 improved its potency (Supplementary Figure S7). RESULTS |
|
79 82 SAR experimental_method The IL-17A/HAP complex structure obtained is very consistent with the observed SAR of our identified peptide inhibitors, explaining well how the evolution of the initial phage peptide 1 to HAP and 45 improved its potency (Supplementary Figure S7). RESULTS |
|
170 175 phage experimental_method The IL-17A/HAP complex structure obtained is very consistent with the observed SAR of our identified peptide inhibitors, explaining well how the evolution of the initial phage peptide 1 to HAP and 45 improved its potency (Supplementary Figure S7). RESULTS |
|
176 185 peptide 1 chemical The IL-17A/HAP complex structure obtained is very consistent with the observed SAR of our identified peptide inhibitors, explaining well how the evolution of the initial phage peptide 1 to HAP and 45 improved its potency (Supplementary Figure S7). RESULTS |
|
189 192 HAP chemical The IL-17A/HAP complex structure obtained is very consistent with the observed SAR of our identified peptide inhibitors, explaining well how the evolution of the initial phage peptide 1 to HAP and 45 improved its potency (Supplementary Figure S7). RESULTS |
|
197 199 45 chemical The IL-17A/HAP complex structure obtained is very consistent with the observed SAR of our identified peptide inhibitors, explaining well how the evolution of the initial phage peptide 1 to HAP and 45 improved its potency (Supplementary Figure S7). RESULTS |
|
37 42 Trp12 residue_name_number The important interactions involving Trp12 of HAP explain the >90 times drop in potency of the W12A variant (6 vs 1, Table 1). RESULTS |
|
46 49 HAP chemical The important interactions involving Trp12 of HAP explain the >90 times drop in potency of the W12A variant (6 vs 1, Table 1). RESULTS |
|
95 99 W12A mutant The important interactions involving Trp12 of HAP explain the >90 times drop in potency of the W12A variant (6 vs 1, Table 1). RESULTS |
|
4 15 amphipathic protein_state The amphipathic nature of the HAP β-strand explains the preference of the hydrophilic residues at the 2 and 4 positions of peptides (14, 18, 19, 21 and 23 vs 1 and 22, Table 1). RESULTS |
|
30 33 HAP chemical The amphipathic nature of the HAP β-strand explains the preference of the hydrophilic residues at the 2 and 4 positions of peptides (14, 18, 19, 21 and 23 vs 1 and 22, Table 1). RESULTS |
|
34 42 β-strand structure_element The amphipathic nature of the HAP β-strand explains the preference of the hydrophilic residues at the 2 and 4 positions of peptides (14, 18, 19, 21 and 23 vs 1 and 22, Table 1). RESULTS |
|
102 103 2 residue_number The amphipathic nature of the HAP β-strand explains the preference of the hydrophilic residues at the 2 and 4 positions of peptides (14, 18, 19, 21 and 23 vs 1 and 22, Table 1). RESULTS |
|
108 109 4 residue_number The amphipathic nature of the HAP β-strand explains the preference of the hydrophilic residues at the 2 and 4 positions of peptides (14, 18, 19, 21 and 23 vs 1 and 22, Table 1). RESULTS |
|
133 135 14 chemical The amphipathic nature of the HAP β-strand explains the preference of the hydrophilic residues at the 2 and 4 positions of peptides (14, 18, 19, 21 and 23 vs 1 and 22, Table 1). RESULTS |
|
137 139 18 chemical The amphipathic nature of the HAP β-strand explains the preference of the hydrophilic residues at the 2 and 4 positions of peptides (14, 18, 19, 21 and 23 vs 1 and 22, Table 1). RESULTS |
|
141 143 19 chemical The amphipathic nature of the HAP β-strand explains the preference of the hydrophilic residues at the 2 and 4 positions of peptides (14, 18, 19, 21 and 23 vs 1 and 22, Table 1). RESULTS |
|
145 147 21 chemical The amphipathic nature of the HAP β-strand explains the preference of the hydrophilic residues at the 2 and 4 positions of peptides (14, 18, 19, 21 and 23 vs 1 and 22, Table 1). RESULTS |
|
152 154 23 chemical The amphipathic nature of the HAP β-strand explains the preference of the hydrophilic residues at the 2 and 4 positions of peptides (14, 18, 19, 21 and 23 vs 1 and 22, Table 1). RESULTS |
|
158 159 1 chemical The amphipathic nature of the HAP β-strand explains the preference of the hydrophilic residues at the 2 and 4 positions of peptides (14, 18, 19, 21 and 23 vs 1 and 22, Table 1). RESULTS |
|
164 166 22 chemical The amphipathic nature of the HAP β-strand explains the preference of the hydrophilic residues at the 2 and 4 positions of peptides (14, 18, 19, 21 and 23 vs 1 and 22, Table 1). RESULTS |
|
27 30 HAP chemical All N-terminal residues of HAP are part of the β-sheet with β-stands 0 and 4 of IL-17A, which explains why removal of the first 1–3 residues completely abolishes the ability of HAP to block IL-17A cell signaling (31,32 and 33, Table 2). RESULTS |
|
47 54 β-sheet structure_element All N-terminal residues of HAP are part of the β-sheet with β-stands 0 and 4 of IL-17A, which explains why removal of the first 1–3 residues completely abolishes the ability of HAP to block IL-17A cell signaling (31,32 and 33, Table 2). RESULTS |
|
60 76 β-stands 0 and 4 structure_element All N-terminal residues of HAP are part of the β-sheet with β-stands 0 and 4 of IL-17A, which explains why removal of the first 1–3 residues completely abolishes the ability of HAP to block IL-17A cell signaling (31,32 and 33, Table 2). RESULTS |
|
80 86 IL-17A protein All N-terminal residues of HAP are part of the β-sheet with β-stands 0 and 4 of IL-17A, which explains why removal of the first 1–3 residues completely abolishes the ability of HAP to block IL-17A cell signaling (31,32 and 33, Table 2). RESULTS |
|
107 117 removal of experimental_method All N-terminal residues of HAP are part of the β-sheet with β-stands 0 and 4 of IL-17A, which explains why removal of the first 1–3 residues completely abolishes the ability of HAP to block IL-17A cell signaling (31,32 and 33, Table 2). RESULTS |
|
122 140 first 1–3 residues residue_range All N-terminal residues of HAP are part of the β-sheet with β-stands 0 and 4 of IL-17A, which explains why removal of the first 1–3 residues completely abolishes the ability of HAP to block IL-17A cell signaling (31,32 and 33, Table 2). RESULTS |
|
177 180 HAP chemical All N-terminal residues of HAP are part of the β-sheet with β-stands 0 and 4 of IL-17A, which explains why removal of the first 1–3 residues completely abolishes the ability of HAP to block IL-17A cell signaling (31,32 and 33, Table 2). RESULTS |
|
190 196 IL-17A protein All N-terminal residues of HAP are part of the β-sheet with β-stands 0 and 4 of IL-17A, which explains why removal of the first 1–3 residues completely abolishes the ability of HAP to block IL-17A cell signaling (31,32 and 33, Table 2). RESULTS |
|
213 215 31 chemical All N-terminal residues of HAP are part of the β-sheet with β-stands 0 and 4 of IL-17A, which explains why removal of the first 1–3 residues completely abolishes the ability of HAP to block IL-17A cell signaling (31,32 and 33, Table 2). RESULTS |
|
216 218 32 chemical All N-terminal residues of HAP are part of the β-sheet with β-stands 0 and 4 of IL-17A, which explains why removal of the first 1–3 residues completely abolishes the ability of HAP to block IL-17A cell signaling (31,32 and 33, Table 2). RESULTS |
|
223 225 33 chemical All N-terminal residues of HAP are part of the β-sheet with β-stands 0 and 4 of IL-17A, which explains why removal of the first 1–3 residues completely abolishes the ability of HAP to block IL-17A cell signaling (31,32 and 33, Table 2). RESULTS |
|
15 20 Asn14 residue_name_number The C-terminal Asn14 and Lys15 of HAP are not directly involved in interactions with IL-17A, and this is reflected in the gradual reduction in activity caused by C-terminal truncations (35 and 36, Table 2). RESULTS |
|
25 30 Lys15 residue_name_number The C-terminal Asn14 and Lys15 of HAP are not directly involved in interactions with IL-17A, and this is reflected in the gradual reduction in activity caused by C-terminal truncations (35 and 36, Table 2). RESULTS |
|
34 37 HAP chemical The C-terminal Asn14 and Lys15 of HAP are not directly involved in interactions with IL-17A, and this is reflected in the gradual reduction in activity caused by C-terminal truncations (35 and 36, Table 2). RESULTS |
|
85 91 IL-17A protein The C-terminal Asn14 and Lys15 of HAP are not directly involved in interactions with IL-17A, and this is reflected in the gradual reduction in activity caused by C-terminal truncations (35 and 36, Table 2). RESULTS |
|
173 184 truncations experimental_method The C-terminal Asn14 and Lys15 of HAP are not directly involved in interactions with IL-17A, and this is reflected in the gradual reduction in activity caused by C-terminal truncations (35 and 36, Table 2). RESULTS |
|
186 188 35 chemical The C-terminal Asn14 and Lys15 of HAP are not directly involved in interactions with IL-17A, and this is reflected in the gradual reduction in activity caused by C-terminal truncations (35 and 36, Table 2). RESULTS |
|
193 195 36 chemical The C-terminal Asn14 and Lys15 of HAP are not directly involved in interactions with IL-17A, and this is reflected in the gradual reduction in activity caused by C-terminal truncations (35 and 36, Table 2). RESULTS |
|
13 20 monomer oligomeric_state Each peptide monomer in 45 may not necessarily be more potent than HAP, but two monomer peptides within the same molecule that can simultaneously bind to IL-17A can greatly improve its potency due to avidity effects. RESULTS |
|
24 26 45 chemical Each peptide monomer in 45 may not necessarily be more potent than HAP, but two monomer peptides within the same molecule that can simultaneously bind to IL-17A can greatly improve its potency due to avidity effects. RESULTS |
|
67 70 HAP chemical Each peptide monomer in 45 may not necessarily be more potent than HAP, but two monomer peptides within the same molecule that can simultaneously bind to IL-17A can greatly improve its potency due to avidity effects. RESULTS |
|
80 87 monomer oligomeric_state Each peptide monomer in 45 may not necessarily be more potent than HAP, but two monomer peptides within the same molecule that can simultaneously bind to IL-17A can greatly improve its potency due to avidity effects. RESULTS |
|
154 160 IL-17A protein Each peptide monomer in 45 may not necessarily be more potent than HAP, but two monomer peptides within the same molecule that can simultaneously bind to IL-17A can greatly improve its potency due to avidity effects. RESULTS |
|
0 3 HAP chemical HAP targets region I of IL-17A, an area that has the least sequence conservation in IL-17 cytokines. RESULTS |
|
12 20 region I structure_element HAP targets region I of IL-17A, an area that has the least sequence conservation in IL-17 cytokines. RESULTS |
|
24 30 IL-17A protein HAP targets region I of IL-17A, an area that has the least sequence conservation in IL-17 cytokines. RESULTS |
|
84 99 IL-17 cytokines protein_type HAP targets region I of IL-17A, an area that has the least sequence conservation in IL-17 cytokines. RESULTS |
|
42 58 HAP binding site site This lack of sequence conservation in the HAP binding site explains the observed specificity of HAP binding to human IL-17A. RESULTS |
|
96 99 HAP chemical This lack of sequence conservation in the HAP binding site explains the observed specificity of HAP binding to human IL-17A. RESULTS |
|
111 116 human species This lack of sequence conservation in the HAP binding site explains the observed specificity of HAP binding to human IL-17A. RESULTS |
|
117 123 IL-17A protein This lack of sequence conservation in the HAP binding site explains the observed specificity of HAP binding to human IL-17A. RESULTS |
|
41 47 IL-17F protein For example, inspection of the published IL-17F crystal structure (PDB code 1JPY) revealed a pocket of IL-17F similar to that of IL-17A for W12 of HAP binding, but it is occupied by a Phe-Phe motif at the N-terminal peptide of IL-17F. RESULTS |
|
48 65 crystal structure evidence For example, inspection of the published IL-17F crystal structure (PDB code 1JPY) revealed a pocket of IL-17F similar to that of IL-17A for W12 of HAP binding, but it is occupied by a Phe-Phe motif at the N-terminal peptide of IL-17F. RESULTS |
|
93 99 pocket site For example, inspection of the published IL-17F crystal structure (PDB code 1JPY) revealed a pocket of IL-17F similar to that of IL-17A for W12 of HAP binding, but it is occupied by a Phe-Phe motif at the N-terminal peptide of IL-17F. RESULTS |
|
103 109 IL-17F protein For example, inspection of the published IL-17F crystal structure (PDB code 1JPY) revealed a pocket of IL-17F similar to that of IL-17A for W12 of HAP binding, but it is occupied by a Phe-Phe motif at the N-terminal peptide of IL-17F. RESULTS |
|
129 135 IL-17A protein For example, inspection of the published IL-17F crystal structure (PDB code 1JPY) revealed a pocket of IL-17F similar to that of IL-17A for W12 of HAP binding, but it is occupied by a Phe-Phe motif at the N-terminal peptide of IL-17F. RESULTS |
|
140 143 W12 residue_name_number For example, inspection of the published IL-17F crystal structure (PDB code 1JPY) revealed a pocket of IL-17F similar to that of IL-17A for W12 of HAP binding, but it is occupied by a Phe-Phe motif at the N-terminal peptide of IL-17F. RESULTS |
|
147 150 HAP chemical For example, inspection of the published IL-17F crystal structure (PDB code 1JPY) revealed a pocket of IL-17F similar to that of IL-17A for W12 of HAP binding, but it is occupied by a Phe-Phe motif at the N-terminal peptide of IL-17F. RESULTS |
|
184 197 Phe-Phe motif structure_element For example, inspection of the published IL-17F crystal structure (PDB code 1JPY) revealed a pocket of IL-17F similar to that of IL-17A for W12 of HAP binding, but it is occupied by a Phe-Phe motif at the N-terminal peptide of IL-17F. RESULTS |
|
227 233 IL-17F protein For example, inspection of the published IL-17F crystal structure (PDB code 1JPY) revealed a pocket of IL-17F similar to that of IL-17A for W12 of HAP binding, but it is occupied by a Phe-Phe motif at the N-terminal peptide of IL-17F. RESULTS |
|
5 18 Phe-Phe motif structure_element This Phe-Phe motif is missing in IL-17A. RESULTS |
|
22 29 missing protein_state This Phe-Phe motif is missing in IL-17A. RESULTS |
|
33 39 IL-17A protein This Phe-Phe motif is missing in IL-17A. RESULTS |
|
0 19 Sequence alignments experimental_method Sequence alignments between human and mouse IL-17A indicated that among IL-17A residues that interacting with HAP, majority differences occur in strand 0 of IL-17A which interacts with the N-terminal β-strand of HAP. RESULTS |
|
28 33 human species Sequence alignments between human and mouse IL-17A indicated that among IL-17A residues that interacting with HAP, majority differences occur in strand 0 of IL-17A which interacts with the N-terminal β-strand of HAP. RESULTS |
|
38 43 mouse taxonomy_domain Sequence alignments between human and mouse IL-17A indicated that among IL-17A residues that interacting with HAP, majority differences occur in strand 0 of IL-17A which interacts with the N-terminal β-strand of HAP. RESULTS |
|
44 50 IL-17A protein Sequence alignments between human and mouse IL-17A indicated that among IL-17A residues that interacting with HAP, majority differences occur in strand 0 of IL-17A which interacts with the N-terminal β-strand of HAP. RESULTS |
|
72 78 IL-17A protein Sequence alignments between human and mouse IL-17A indicated that among IL-17A residues that interacting with HAP, majority differences occur in strand 0 of IL-17A which interacts with the N-terminal β-strand of HAP. RESULTS |
|
110 113 HAP chemical Sequence alignments between human and mouse IL-17A indicated that among IL-17A residues that interacting with HAP, majority differences occur in strand 0 of IL-17A which interacts with the N-terminal β-strand of HAP. RESULTS |
|
145 153 strand 0 structure_element Sequence alignments between human and mouse IL-17A indicated that among IL-17A residues that interacting with HAP, majority differences occur in strand 0 of IL-17A which interacts with the N-terminal β-strand of HAP. RESULTS |
|
157 163 IL-17A protein Sequence alignments between human and mouse IL-17A indicated that among IL-17A residues that interacting with HAP, majority differences occur in strand 0 of IL-17A which interacts with the N-terminal β-strand of HAP. RESULTS |
|
200 208 β-strand structure_element Sequence alignments between human and mouse IL-17A indicated that among IL-17A residues that interacting with HAP, majority differences occur in strand 0 of IL-17A which interacts with the N-terminal β-strand of HAP. RESULTS |
|
212 215 HAP chemical Sequence alignments between human and mouse IL-17A indicated that among IL-17A residues that interacting with HAP, majority differences occur in strand 0 of IL-17A which interacts with the N-terminal β-strand of HAP. RESULTS |
|
3 8 human species In human IL-17A the sequences are 21TVMVNLNI, and in mouse they are 21NVKVNLKV. RESULTS |
|
9 15 IL-17A protein In human IL-17A the sequences are 21TVMVNLNI, and in mouse they are 21NVKVNLKV. RESULTS |
|
34 44 21TVMVNLNI chemical In human IL-17A the sequences are 21TVMVNLNI, and in mouse they are 21NVKVNLKV. RESULTS |
|
53 58 mouse taxonomy_domain In human IL-17A the sequences are 21TVMVNLNI, and in mouse they are 21NVKVNLKV. RESULTS |
|
68 78 21NVKVNLKV chemical In human IL-17A the sequences are 21TVMVNLNI, and in mouse they are 21NVKVNLKV. RESULTS |
|
23 36 phage display experimental_method Using a combination of phage display and SAR we have discovered novel peptides that are IL-17A antagonists. DISCUSS |
|
41 44 SAR experimental_method Using a combination of phage display and SAR we have discovered novel peptides that are IL-17A antagonists. DISCUSS |
|
88 94 IL-17A protein Using a combination of phage display and SAR we have discovered novel peptides that are IL-17A antagonists. DISCUSS |
|
23 26 HAP chemical One of those peptides, HAP, also shows activity in inhibiting the production of multiple inflammatory cytokines by primary human keratinocytes stimulated by IL-17A and TNF-α, a disease relevant-model. DISCUSS |
|
102 111 cytokines protein_type One of those peptides, HAP, also shows activity in inhibiting the production of multiple inflammatory cytokines by primary human keratinocytes stimulated by IL-17A and TNF-α, a disease relevant-model. DISCUSS |
|
123 128 human species One of those peptides, HAP, also shows activity in inhibiting the production of multiple inflammatory cytokines by primary human keratinocytes stimulated by IL-17A and TNF-α, a disease relevant-model. DISCUSS |
|
157 163 IL-17A protein One of those peptides, HAP, also shows activity in inhibiting the production of multiple inflammatory cytokines by primary human keratinocytes stimulated by IL-17A and TNF-α, a disease relevant-model. DISCUSS |
|
168 173 TNF-α protein One of those peptides, HAP, also shows activity in inhibiting the production of multiple inflammatory cytokines by primary human keratinocytes stimulated by IL-17A and TNF-α, a disease relevant-model. DISCUSS |
|
13 23 determined experimental_method We have also determined the complex structure of IL-17A/HAP, which provides the structural basis for HAP’s antagonism to IL-17A signaling. DISCUSS |
|
28 45 complex structure evidence We have also determined the complex structure of IL-17A/HAP, which provides the structural basis for HAP’s antagonism to IL-17A signaling. DISCUSS |
|
49 59 IL-17A/HAP complex_assembly We have also determined the complex structure of IL-17A/HAP, which provides the structural basis for HAP’s antagonism to IL-17A signaling. DISCUSS |
|
101 104 HAP chemical We have also determined the complex structure of IL-17A/HAP, which provides the structural basis for HAP’s antagonism to IL-17A signaling. DISCUSS |
|
121 127 IL-17A protein We have also determined the complex structure of IL-17A/HAP, which provides the structural basis for HAP’s antagonism to IL-17A signaling. DISCUSS |
|
7 13 IL-17A protein During IL-17A signaling, IL-17A binds to one copy of IL-17RA and one copy of IL-17RC. DISCUSS |
|
25 31 IL-17A protein During IL-17A signaling, IL-17A binds to one copy of IL-17RA and one copy of IL-17RC. DISCUSS |
|
53 60 IL-17RA protein During IL-17A signaling, IL-17A binds to one copy of IL-17RA and one copy of IL-17RC. DISCUSS |
|
77 84 IL-17RC protein During IL-17A signaling, IL-17A binds to one copy of IL-17RA and one copy of IL-17RC. DISCUSS |
|
6 9 apo protein_state Since apo IL-17A is a homodimer with 2 fold symmetry, IL-17RA potentially can bind to either face of the IL-17A dimer. DISCUSS |
|
10 16 IL-17A protein Since apo IL-17A is a homodimer with 2 fold symmetry, IL-17RA potentially can bind to either face of the IL-17A dimer. DISCUSS |
|
22 31 homodimer oligomeric_state Since apo IL-17A is a homodimer with 2 fold symmetry, IL-17RA potentially can bind to either face of the IL-17A dimer. DISCUSS |
|
54 61 IL-17RA protein Since apo IL-17A is a homodimer with 2 fold symmetry, IL-17RA potentially can bind to either face of the IL-17A dimer. DISCUSS |
|
105 111 IL-17A protein Since apo IL-17A is a homodimer with 2 fold symmetry, IL-17RA potentially can bind to either face of the IL-17A dimer. DISCUSS |
|
112 117 dimer oligomeric_state Since apo IL-17A is a homodimer with 2 fold symmetry, IL-17RA potentially can bind to either face of the IL-17A dimer. DISCUSS |
|
9 12 HAP chemical With two HAP molecules covering both faces of the IL-17A dimer, HAP can block IL-17RA approaching from either face. DISCUSS |
|
50 56 IL-17A protein With two HAP molecules covering both faces of the IL-17A dimer, HAP can block IL-17RA approaching from either face. DISCUSS |
|
57 62 dimer oligomeric_state With two HAP molecules covering both faces of the IL-17A dimer, HAP can block IL-17RA approaching from either face. DISCUSS |
|
64 67 HAP chemical With two HAP molecules covering both faces of the IL-17A dimer, HAP can block IL-17RA approaching from either face. DISCUSS |
|
78 85 IL-17RA protein With two HAP molecules covering both faces of the IL-17A dimer, HAP can block IL-17RA approaching from either face. DISCUSS |
|
36 53 crystal structure evidence To form the 1:2 complex observed in crystal structure, it is important that there is no strong negative cooperativity in the binding of two HAP molecules. DISCUSS |
|
140 143 HAP chemical To form the 1:2 complex observed in crystal structure, it is important that there is no strong negative cooperativity in the binding of two HAP molecules. DISCUSS |
|
12 60 native electrospray ionization mass spectrometry experimental_method In fact, in native electrospray ionization mass spectrometry analysis only 1:2 IL-17A/HAP complex was observed even when IL-17A was in excess (Supplementary Figure S8), indicating a positive binding cooperativity that favors inhibition of IL-17RA binding by HAP. DISCUSS |
|
79 89 IL-17A/HAP complex_assembly In fact, in native electrospray ionization mass spectrometry analysis only 1:2 IL-17A/HAP complex was observed even when IL-17A was in excess (Supplementary Figure S8), indicating a positive binding cooperativity that favors inhibition of IL-17RA binding by HAP. DISCUSS |
|
121 127 IL-17A protein In fact, in native electrospray ionization mass spectrometry analysis only 1:2 IL-17A/HAP complex was observed even when IL-17A was in excess (Supplementary Figure S8), indicating a positive binding cooperativity that favors inhibition of IL-17RA binding by HAP. DISCUSS |
|
239 246 IL-17RA protein In fact, in native electrospray ionization mass spectrometry analysis only 1:2 IL-17A/HAP complex was observed even when IL-17A was in excess (Supplementary Figure S8), indicating a positive binding cooperativity that favors inhibition of IL-17RA binding by HAP. DISCUSS |
|
258 261 HAP chemical In fact, in native electrospray ionization mass spectrometry analysis only 1:2 IL-17A/HAP complex was observed even when IL-17A was in excess (Supplementary Figure S8), indicating a positive binding cooperativity that favors inhibition of IL-17RA binding by HAP. DISCUSS |
|
0 3 HAP chemical HAP, with only 15 residues, can achieve almost the same binding affinity as the much larger IL-17RA molecule, indicating a more efficient way of binding to IL-17A. DISCUSS |
|
15 26 15 residues residue_range HAP, with only 15 residues, can achieve almost the same binding affinity as the much larger IL-17RA molecule, indicating a more efficient way of binding to IL-17A. DISCUSS |
|
56 72 binding affinity evidence HAP, with only 15 residues, can achieve almost the same binding affinity as the much larger IL-17RA molecule, indicating a more efficient way of binding to IL-17A. DISCUSS |
|
92 99 IL-17RA protein HAP, with only 15 residues, can achieve almost the same binding affinity as the much larger IL-17RA molecule, indicating a more efficient way of binding to IL-17A. DISCUSS |
|
156 162 IL-17A protein HAP, with only 15 residues, can achieve almost the same binding affinity as the much larger IL-17RA molecule, indicating a more efficient way of binding to IL-17A. DISCUSS |
|
19 25 IL-17A protein The interaction of IL-17A with IL-17RA has an extensive interface, covering ~2,200 Å2 surface area of IL-17A. DISCUSS |
|
31 38 IL-17RA protein The interaction of IL-17A with IL-17RA has an extensive interface, covering ~2,200 Å2 surface area of IL-17A. DISCUSS |
|
56 65 interface site The interaction of IL-17A with IL-17RA has an extensive interface, covering ~2,200 Å2 surface area of IL-17A. DISCUSS |
|
102 108 IL-17A protein The interaction of IL-17A with IL-17RA has an extensive interface, covering ~2,200 Å2 surface area of IL-17A. DISCUSS |
|
39 71 IL-17A/IL-17RA binding interface site Due to the discontinuous nature of the IL-17A/IL-17RA binding interface, it is classified as having tertiary structural epitopes on both binding partners, and is therefore hard to target using small molecules. DISCUSS |
|
15 18 HAP chemical Our studies of HAP demonstrated an uncommon mode of action for a peptide in inhibiting such a difficult protein-protein interaction target, and suggest further possible improvements in its binding potency. DISCUSS |
|
29 32 HAP chemical One way of further improving HAP’s potency is by dimerization. DISCUSS |
|
21 24 HAP chemical Homo-dimerization of HAP (45) achieved sub-nanomolar potency against human IL-17A in cell assay. DISCUSS |
|
26 28 45 chemical Homo-dimerization of HAP (45) achieved sub-nanomolar potency against human IL-17A in cell assay. DISCUSS |
|
69 74 human species Homo-dimerization of HAP (45) achieved sub-nanomolar potency against human IL-17A in cell assay. DISCUSS |
|
75 81 IL-17A protein Homo-dimerization of HAP (45) achieved sub-nanomolar potency against human IL-17A in cell assay. DISCUSS |
|
7 24 crystal structure evidence In the crystal structure, the distance between the carbonyl of Asn14 of one HAP molecule and the N-terminus of the second is only 15.7 Å, suggesting the potential for more potent dimeric peptides to be designed by using linkers of different lengths at different positions. DISCUSS |
|
63 68 Asn14 residue_name_number In the crystal structure, the distance between the carbonyl of Asn14 of one HAP molecule and the N-terminus of the second is only 15.7 Å, suggesting the potential for more potent dimeric peptides to be designed by using linkers of different lengths at different positions. DISCUSS |
|
76 79 HAP chemical In the crystal structure, the distance between the carbonyl of Asn14 of one HAP molecule and the N-terminus of the second is only 15.7 Å, suggesting the potential for more potent dimeric peptides to be designed by using linkers of different lengths at different positions. DISCUSS |
|
179 186 dimeric oligomeric_state In the crystal structure, the distance between the carbonyl of Asn14 of one HAP molecule and the N-terminus of the second is only 15.7 Å, suggesting the potential for more potent dimeric peptides to be designed by using linkers of different lengths at different positions. DISCUSS |
|
187 195 peptides chemical In the crystal structure, the distance between the carbonyl of Asn14 of one HAP molecule and the N-terminus of the second is only 15.7 Å, suggesting the potential for more potent dimeric peptides to be designed by using linkers of different lengths at different positions. DISCUSS |
|
31 34 HAP chemical Another direction of improving HAP is by reducing its size. DISCUSS |
|
23 40 crystal structure evidence As demonstrated by the crystal structure, binding of the α-helix of HAP should be sufficient for preventing IL-17RA binding to IL-17A. DISCUSS |
|
57 64 α-helix structure_element As demonstrated by the crystal structure, binding of the α-helix of HAP should be sufficient for preventing IL-17RA binding to IL-17A. DISCUSS |
|
68 71 HAP chemical As demonstrated by the crystal structure, binding of the α-helix of HAP should be sufficient for preventing IL-17RA binding to IL-17A. DISCUSS |
|
108 115 IL-17RA protein As demonstrated by the crystal structure, binding of the α-helix of HAP should be sufficient for preventing IL-17RA binding to IL-17A. DISCUSS |
|
127 133 IL-17A protein As demonstrated by the crystal structure, binding of the α-helix of HAP should be sufficient for preventing IL-17RA binding to IL-17A. DISCUSS |
|
94 101 α-helix structure_element Theoretically, it is possible to design chemicals such as stapled α-helical peptides to block α-helix-mediated IL-17A/IL-17RA interactions. DISCUSS |
|
111 125 IL-17A/IL-17RA complex_assembly Theoretically, it is possible to design chemicals such as stapled α-helical peptides to block α-helix-mediated IL-17A/IL-17RA interactions. DISCUSS |
|
37 43 IL-17A protein In summary, these peptide-based anti-IL-17A modalities could be further developed as alternative therapeutic options to the reported monoclonal antibodies. DISCUSS |
|
144 154 antibodies protein_type In summary, these peptide-based anti-IL-17A modalities could be further developed as alternative therapeutic options to the reported monoclonal antibodies. DISCUSS |
|
67 73 IL-17A protein We are also very interested in finding non-peptidic small molecule IL-17A antagonists, and HAP can be used as an excellent tool peptide. DISCUSS |
|
91 94 HAP chemical We are also very interested in finding non-peptidic small molecule IL-17A antagonists, and HAP can be used as an excellent tool peptide. DISCUSS |
|
48 58 structures evidence The strategy utilized in generating the complex structures of HAP may also be useful for enabling structure based design of some known small molecule IL-17A antagonists. DISCUSS |
|
62 65 HAP chemical The strategy utilized in generating the complex structures of HAP may also be useful for enabling structure based design of some known small molecule IL-17A antagonists. DISCUSS |
|
11 14 HAP chemical Binding of HAP to IL-17A and inhibition of IL-17A/IL-17RA are measured by SPR, FRET and cell-based assays. FIG |
|
18 24 IL-17A protein Binding of HAP to IL-17A and inhibition of IL-17A/IL-17RA are measured by SPR, FRET and cell-based assays. FIG |
|
43 57 IL-17A/IL-17RA complex_assembly Binding of HAP to IL-17A and inhibition of IL-17A/IL-17RA are measured by SPR, FRET and cell-based assays. FIG |
|
74 77 SPR experimental_method Binding of HAP to IL-17A and inhibition of IL-17A/IL-17RA are measured by SPR, FRET and cell-based assays. FIG |
|
79 83 FRET experimental_method Binding of HAP to IL-17A and inhibition of IL-17A/IL-17RA are measured by SPR, FRET and cell-based assays. FIG |
|
88 105 cell-based assays experimental_method Binding of HAP to IL-17A and inhibition of IL-17A/IL-17RA are measured by SPR, FRET and cell-based assays. FIG |
|
12 15 SPR experimental_method (A) Typical SPR sensorgrams (black) of HAP at indicated concentrations binding to biotinylated human IL-17A immobilized on a streptavidin chip surface, fitted with single site binding model curves (red). FIG |
|
16 27 sensorgrams evidence (A) Typical SPR sensorgrams (black) of HAP at indicated concentrations binding to biotinylated human IL-17A immobilized on a streptavidin chip surface, fitted with single site binding model curves (red). FIG |
|
39 42 HAP chemical (A) Typical SPR sensorgrams (black) of HAP at indicated concentrations binding to biotinylated human IL-17A immobilized on a streptavidin chip surface, fitted with single site binding model curves (red). FIG |
|
82 94 biotinylated protein_state (A) Typical SPR sensorgrams (black) of HAP at indicated concentrations binding to biotinylated human IL-17A immobilized on a streptavidin chip surface, fitted with single site binding model curves (red). FIG |
|
95 100 human species (A) Typical SPR sensorgrams (black) of HAP at indicated concentrations binding to biotinylated human IL-17A immobilized on a streptavidin chip surface, fitted with single site binding model curves (red). FIG |
|
101 107 IL-17A protein (A) Typical SPR sensorgrams (black) of HAP at indicated concentrations binding to biotinylated human IL-17A immobilized on a streptavidin chip surface, fitted with single site binding model curves (red). FIG |
|
164 196 single site binding model curves evidence (A) Typical SPR sensorgrams (black) of HAP at indicated concentrations binding to biotinylated human IL-17A immobilized on a streptavidin chip surface, fitted with single site binding model curves (red). FIG |
|
20 22 ka evidence Kinetic parameters (ka, kd) were obtained by a global fit using three concentrations in triplicate. FIG |
|
24 26 kd evidence Kinetic parameters (ka, kd) were obtained by a global fit using three concentrations in triplicate. FIG |
|
0 2 KD evidence KD determined by the standard equation, KD = kd/ka. (B) HAP inhibits SPR signaling of IL-17A binding to immobilized IL-17RA. FIG |
|
40 42 KD evidence KD determined by the standard equation, KD = kd/ka. (B) HAP inhibits SPR signaling of IL-17A binding to immobilized IL-17RA. FIG |
|
45 47 kd evidence KD determined by the standard equation, KD = kd/ka. (B) HAP inhibits SPR signaling of IL-17A binding to immobilized IL-17RA. FIG |
|
48 50 ka evidence KD determined by the standard equation, KD = kd/ka. (B) HAP inhibits SPR signaling of IL-17A binding to immobilized IL-17RA. FIG |
|
56 59 HAP chemical KD determined by the standard equation, KD = kd/ka. (B) HAP inhibits SPR signaling of IL-17A binding to immobilized IL-17RA. FIG |
|
69 72 SPR experimental_method KD determined by the standard equation, KD = kd/ka. (B) HAP inhibits SPR signaling of IL-17A binding to immobilized IL-17RA. FIG |
|
86 92 IL-17A protein KD determined by the standard equation, KD = kd/ka. (B) HAP inhibits SPR signaling of IL-17A binding to immobilized IL-17RA. FIG |
|
104 115 immobilized protein_state KD determined by the standard equation, KD = kd/ka. (B) HAP inhibits SPR signaling of IL-17A binding to immobilized IL-17RA. FIG |
|
116 123 IL-17RA protein KD determined by the standard equation, KD = kd/ka. (B) HAP inhibits SPR signaling of IL-17A binding to immobilized IL-17RA. FIG |
|
96 102 IL-17A protein Data are mean and error bars of +/− standard deviation of three measurements. (C) Inhibition of IL-17A and IL-17RA binding by HAP measured by FRET assay. FIG |
|
107 114 IL-17RA protein Data are mean and error bars of +/− standard deviation of three measurements. (C) Inhibition of IL-17A and IL-17RA binding by HAP measured by FRET assay. FIG |
|
126 129 HAP chemical Data are mean and error bars of +/− standard deviation of three measurements. (C) Inhibition of IL-17A and IL-17RA binding by HAP measured by FRET assay. FIG |
|
142 152 FRET assay experimental_method Data are mean and error bars of +/− standard deviation of three measurements. (C) Inhibition of IL-17A and IL-17RA binding by HAP measured by FRET assay. FIG |
|
121 124 HAP chemical Data are mean and error bars of +/− standard deviation from 299 experiments, each performed in duplicate. (D) Example of HAP selective inhibition of the production of IL-8 (triangles), IL-6 (squares) and CCL-20 (circles) by primary human keratinocyte cells synergistically stimulated by 100 ng/ml IL-17A and 10 ng/ml TNF-α. FIG |
|
167 171 IL-8 protein_type Data are mean and error bars of +/− standard deviation from 299 experiments, each performed in duplicate. (D) Example of HAP selective inhibition of the production of IL-8 (triangles), IL-6 (squares) and CCL-20 (circles) by primary human keratinocyte cells synergistically stimulated by 100 ng/ml IL-17A and 10 ng/ml TNF-α. FIG |
|
185 189 IL-6 protein_type Data are mean and error bars of +/− standard deviation from 299 experiments, each performed in duplicate. (D) Example of HAP selective inhibition of the production of IL-8 (triangles), IL-6 (squares) and CCL-20 (circles) by primary human keratinocyte cells synergistically stimulated by 100 ng/ml IL-17A and 10 ng/ml TNF-α. FIG |
|
204 210 CCL-20 protein_type Data are mean and error bars of +/− standard deviation from 299 experiments, each performed in duplicate. (D) Example of HAP selective inhibition of the production of IL-8 (triangles), IL-6 (squares) and CCL-20 (circles) by primary human keratinocyte cells synergistically stimulated by 100 ng/ml IL-17A and 10 ng/ml TNF-α. FIG |
|
232 237 human species Data are mean and error bars of +/− standard deviation from 299 experiments, each performed in duplicate. (D) Example of HAP selective inhibition of the production of IL-8 (triangles), IL-6 (squares) and CCL-20 (circles) by primary human keratinocyte cells synergistically stimulated by 100 ng/ml IL-17A and 10 ng/ml TNF-α. FIG |
|
297 303 IL-17A protein Data are mean and error bars of +/− standard deviation from 299 experiments, each performed in duplicate. (D) Example of HAP selective inhibition of the production of IL-8 (triangles), IL-6 (squares) and CCL-20 (circles) by primary human keratinocyte cells synergistically stimulated by 100 ng/ml IL-17A and 10 ng/ml TNF-α. FIG |
|
317 322 TNF-α protein Data are mean and error bars of +/− standard deviation from 299 experiments, each performed in duplicate. (D) Example of HAP selective inhibition of the production of IL-8 (triangles), IL-6 (squares) and CCL-20 (circles) by primary human keratinocyte cells synergistically stimulated by 100 ng/ml IL-17A and 10 ng/ml TNF-α. FIG |
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0 3 HAP chemical HAP does not inhibit the baseline production of IL-6, IL-8 and CCL-20 stimulated by 10 ng/ml TNF-α alone (gray lines and symbols). FIG |
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48 52 IL-6 protein_type HAP does not inhibit the baseline production of IL-6, IL-8 and CCL-20 stimulated by 10 ng/ml TNF-α alone (gray lines and symbols). FIG |
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54 58 IL-8 protein_type HAP does not inhibit the baseline production of IL-6, IL-8 and CCL-20 stimulated by 10 ng/ml TNF-α alone (gray lines and symbols). FIG |
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63 69 CCL-20 protein_type HAP does not inhibit the baseline production of IL-6, IL-8 and CCL-20 stimulated by 10 ng/ml TNF-α alone (gray lines and symbols). FIG |
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93 98 TNF-α protein HAP does not inhibit the baseline production of IL-6, IL-8 and CCL-20 stimulated by 10 ng/ml TNF-α alone (gray lines and symbols). FIG |
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8 17 structure evidence Overall structure of the Fab/IL-17A/HAP complex in ribbon presentation. FIG |
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25 39 Fab/IL-17A/HAP complex_assembly Overall structure of the Fab/IL-17A/HAP complex in ribbon presentation. FIG |
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4 7 HAP chemical Two HAP molecules are colored blue and red, and IL-17A monomers are colored ice blue and pink, respectively. FIG |
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48 54 IL-17A protein Two HAP molecules are colored blue and red, and IL-17A monomers are colored ice blue and pink, respectively. FIG |
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55 63 monomers oligomeric_state Two HAP molecules are colored blue and red, and IL-17A monomers are colored ice blue and pink, respectively. FIG |
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29 42 binding sites site (A) Overview of the distinct binding sites of Fab and HAP to IL-17A. FIG |
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46 49 Fab structure_element (A) Overview of the distinct binding sites of Fab and HAP to IL-17A. FIG |
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54 57 HAP chemical (A) Overview of the distinct binding sites of Fab and HAP to IL-17A. FIG |
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61 67 IL-17A protein (A) Overview of the distinct binding sites of Fab and HAP to IL-17A. FIG |
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25 35 IL-17A/HAP complex_assembly (B) Close-in view of the IL-17A/HAP structure. FIG |
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36 45 structure evidence (B) Close-in view of the IL-17A/HAP structure. FIG |
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0 6 IL-17A protein IL-17A β-strands are labelled. FIG |
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7 16 β-strands structure_element IL-17A β-strands are labelled. FIG |
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16 21 bound protein_state Each of the two bound HAP interacts with both monomers of the IL-17A dimer. FIG |
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22 25 HAP chemical Each of the two bound HAP interacts with both monomers of the IL-17A dimer. FIG |
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46 54 monomers oligomeric_state Each of the two bound HAP interacts with both monomers of the IL-17A dimer. FIG |
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62 68 IL-17A protein Each of the two bound HAP interacts with both monomers of the IL-17A dimer. FIG |
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69 74 dimer oligomeric_state Each of the two bound HAP interacts with both monomers of the IL-17A dimer. FIG |
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25 39 IL-17A/IL-17RA complex_assembly (C) As a comparison, the IL-17A/IL-17RA complex was shown with IL-17A in the same orientation. FIG |
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63 69 IL-17A protein (C) As a comparison, the IL-17A/IL-17RA complex was shown with IL-17A in the same orientation. FIG |
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21 45 IL-17A/IL-17RA interface site Three distinct areas IL-17A/IL-17RA interface are labeled. FIG |
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35 49 IL-17A/IL-17RA complex_assembly Mechanism of the inhibition of the IL-17A/IL-17RA interaction by HAP. FIG |
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65 68 HAP chemical Mechanism of the inhibition of the IL-17A/IL-17RA interaction by HAP. FIG |
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4 7 HAP chemical (A) HAP binds at region I of IL-17A. FIG |
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17 25 region I structure_element (A) HAP binds at region I of IL-17A. FIG |
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29 35 IL-17A protein (A) HAP binds at region I of IL-17A. FIG |
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0 6 IL-17A protein IL-17A dimer is in surface presentation (β-strands 0 shown as ribbons for clarity). FIG |
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7 12 dimer oligomeric_state IL-17A dimer is in surface presentation (β-strands 0 shown as ribbons for clarity). FIG |
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41 52 β-strands 0 structure_element IL-17A dimer is in surface presentation (β-strands 0 shown as ribbons for clarity). FIG |
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0 18 Polar interactions bond_interaction Polar interactions are shown in dashes. FIG |
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0 3 HAP chemical HAP residues as well as key IL-17A residues are labeled. FIG |
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28 34 IL-17A protein HAP residues as well as key IL-17A residues are labeled. FIG |
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19 22 HAP chemical For clarity, a few HAP residues are also shown in stick model with carbon atoms colored green, oxygen in red and nitrogen in blue. FIG |
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4 10 I-17RA protein (B) I-17RA (ribbon in gold) peptide Leu27-Ile32 binds to the same area as the HAP α-helix. FIG |
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36 47 Leu27-Ile32 residue_range (B) I-17RA (ribbon in gold) peptide Leu27-Ile32 binds to the same area as the HAP α-helix. FIG |
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78 81 HAP chemical (B) I-17RA (ribbon in gold) peptide Leu27-Ile32 binds to the same area as the HAP α-helix. FIG |
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82 89 α-helix structure_element (B) I-17RA (ribbon in gold) peptide Leu27-Ile32 binds to the same area as the HAP α-helix. FIG |
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0 5 Trp31 residue_name_number Trp31 of IL-17RA binds to the same pocket in IL-17A as Trp12 of HAP. (C) As illustrated by overlay a single HAP molecule and β-strands 0 (grey) of the IL-17A/HAP complex in the apo IL-17A structure, conformational changes in region I of IL-17A are needed for binding of both the β-stand and α-helix of the HAP. FIG |
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9 16 IL-17RA protein Trp31 of IL-17RA binds to the same pocket in IL-17A as Trp12 of HAP. (C) As illustrated by overlay a single HAP molecule and β-strands 0 (grey) of the IL-17A/HAP complex in the apo IL-17A structure, conformational changes in region I of IL-17A are needed for binding of both the β-stand and α-helix of the HAP. FIG |
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35 41 pocket site Trp31 of IL-17RA binds to the same pocket in IL-17A as Trp12 of HAP. (C) As illustrated by overlay a single HAP molecule and β-strands 0 (grey) of the IL-17A/HAP complex in the apo IL-17A structure, conformational changes in region I of IL-17A are needed for binding of both the β-stand and α-helix of the HAP. FIG |
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45 51 IL-17A protein Trp31 of IL-17RA binds to the same pocket in IL-17A as Trp12 of HAP. (C) As illustrated by overlay a single HAP molecule and β-strands 0 (grey) of the IL-17A/HAP complex in the apo IL-17A structure, conformational changes in region I of IL-17A are needed for binding of both the β-stand and α-helix of the HAP. FIG |
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55 60 Trp12 residue_name_number Trp31 of IL-17RA binds to the same pocket in IL-17A as Trp12 of HAP. (C) As illustrated by overlay a single HAP molecule and β-strands 0 (grey) of the IL-17A/HAP complex in the apo IL-17A structure, conformational changes in region I of IL-17A are needed for binding of both the β-stand and α-helix of the HAP. FIG |
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64 67 HAP chemical Trp31 of IL-17RA binds to the same pocket in IL-17A as Trp12 of HAP. (C) As illustrated by overlay a single HAP molecule and β-strands 0 (grey) of the IL-17A/HAP complex in the apo IL-17A structure, conformational changes in region I of IL-17A are needed for binding of both the β-stand and α-helix of the HAP. FIG |
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91 98 overlay experimental_method Trp31 of IL-17RA binds to the same pocket in IL-17A as Trp12 of HAP. (C) As illustrated by overlay a single HAP molecule and β-strands 0 (grey) of the IL-17A/HAP complex in the apo IL-17A structure, conformational changes in region I of IL-17A are needed for binding of both the β-stand and α-helix of the HAP. FIG |
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108 111 HAP chemical Trp31 of IL-17RA binds to the same pocket in IL-17A as Trp12 of HAP. (C) As illustrated by overlay a single HAP molecule and β-strands 0 (grey) of the IL-17A/HAP complex in the apo IL-17A structure, conformational changes in region I of IL-17A are needed for binding of both the β-stand and α-helix of the HAP. FIG |
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125 136 β-strands 0 structure_element Trp31 of IL-17RA binds to the same pocket in IL-17A as Trp12 of HAP. (C) As illustrated by overlay a single HAP molecule and β-strands 0 (grey) of the IL-17A/HAP complex in the apo IL-17A structure, conformational changes in region I of IL-17A are needed for binding of both the β-stand and α-helix of the HAP. FIG |
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151 161 IL-17A/HAP complex_assembly Trp31 of IL-17RA binds to the same pocket in IL-17A as Trp12 of HAP. (C) As illustrated by overlay a single HAP molecule and β-strands 0 (grey) of the IL-17A/HAP complex in the apo IL-17A structure, conformational changes in region I of IL-17A are needed for binding of both the β-stand and α-helix of the HAP. FIG |
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177 180 apo protein_state Trp31 of IL-17RA binds to the same pocket in IL-17A as Trp12 of HAP. (C) As illustrated by overlay a single HAP molecule and β-strands 0 (grey) of the IL-17A/HAP complex in the apo IL-17A structure, conformational changes in region I of IL-17A are needed for binding of both the β-stand and α-helix of the HAP. FIG |
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181 187 IL-17A protein Trp31 of IL-17RA binds to the same pocket in IL-17A as Trp12 of HAP. (C) As illustrated by overlay a single HAP molecule and β-strands 0 (grey) of the IL-17A/HAP complex in the apo IL-17A structure, conformational changes in region I of IL-17A are needed for binding of both the β-stand and α-helix of the HAP. FIG |
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188 197 structure evidence Trp31 of IL-17RA binds to the same pocket in IL-17A as Trp12 of HAP. (C) As illustrated by overlay a single HAP molecule and β-strands 0 (grey) of the IL-17A/HAP complex in the apo IL-17A structure, conformational changes in region I of IL-17A are needed for binding of both the β-stand and α-helix of the HAP. FIG |
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225 233 region I structure_element Trp31 of IL-17RA binds to the same pocket in IL-17A as Trp12 of HAP. (C) As illustrated by overlay a single HAP molecule and β-strands 0 (grey) of the IL-17A/HAP complex in the apo IL-17A structure, conformational changes in region I of IL-17A are needed for binding of both the β-stand and α-helix of the HAP. FIG |
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237 243 IL-17A protein Trp31 of IL-17RA binds to the same pocket in IL-17A as Trp12 of HAP. (C) As illustrated by overlay a single HAP molecule and β-strands 0 (grey) of the IL-17A/HAP complex in the apo IL-17A structure, conformational changes in region I of IL-17A are needed for binding of both the β-stand and α-helix of the HAP. FIG |
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279 286 β-stand structure_element Trp31 of IL-17RA binds to the same pocket in IL-17A as Trp12 of HAP. (C) As illustrated by overlay a single HAP molecule and β-strands 0 (grey) of the IL-17A/HAP complex in the apo IL-17A structure, conformational changes in region I of IL-17A are needed for binding of both the β-stand and α-helix of the HAP. FIG |
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291 298 α-helix structure_element Trp31 of IL-17RA binds to the same pocket in IL-17A as Trp12 of HAP. (C) As illustrated by overlay a single HAP molecule and β-strands 0 (grey) of the IL-17A/HAP complex in the apo IL-17A structure, conformational changes in region I of IL-17A are needed for binding of both the β-stand and α-helix of the HAP. FIG |
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306 309 HAP chemical Trp31 of IL-17RA binds to the same pocket in IL-17A as Trp12 of HAP. (C) As illustrated by overlay a single HAP molecule and β-strands 0 (grey) of the IL-17A/HAP complex in the apo IL-17A structure, conformational changes in region I of IL-17A are needed for binding of both the β-stand and α-helix of the HAP. FIG |
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16 34 Trp binding pocket site Notice that the Trp binding pocket for W12 of HAP or W31 of IL-17RA is missing in the apo structure. FIG |
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39 42 W12 residue_name_number Notice that the Trp binding pocket for W12 of HAP or W31 of IL-17RA is missing in the apo structure. FIG |
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46 49 HAP chemical Notice that the Trp binding pocket for W12 of HAP or W31 of IL-17RA is missing in the apo structure. FIG |
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53 56 W31 residue_name_number Notice that the Trp binding pocket for W12 of HAP or W31 of IL-17RA is missing in the apo structure. FIG |
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60 67 IL-17RA protein Notice that the Trp binding pocket for W12 of HAP or W31 of IL-17RA is missing in the apo structure. FIG |
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86 89 apo protein_state Notice that the Trp binding pocket for W12 of HAP or W31 of IL-17RA is missing in the apo structure. FIG |
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90 99 structure evidence Notice that the Trp binding pocket for W12 of HAP or W31 of IL-17RA is missing in the apo structure. FIG |
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0 26 ELISA competition activity experimental_method ELISA competition activity of peptide analogues of 1. TABLE |
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