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19 25 IL-17A protein Inhibiting complex IL-17A and IL-17RA interactions with a linear peptide TITLE
30 37 IL-17RA protein Inhibiting complex IL-17A and IL-17RA interactions with a linear peptide TITLE
65 72 peptide chemical Inhibiting complex IL-17A and IL-17RA interactions with a linear peptide TITLE
0 6 IL-17A protein IL-17A is a pro-inflammatory cytokine that has been implicated in autoimmune and inflammatory diseases. ABSTRACT
29 37 cytokine protein_type IL-17A is a pro-inflammatory cytokine that has been implicated in autoimmune and inflammatory diseases. ABSTRACT
11 21 antibodies protein_type Monoclonal antibodies inhibiting IL-17A signaling have demonstrated remarkable efficacy, but an oral therapy is still lacking. ABSTRACT
33 39 IL-17A protein Monoclonal antibodies inhibiting IL-17A signaling have demonstrated remarkable efficacy, but an oral therapy is still lacking. ABSTRACT
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
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
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
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
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
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
0 3 HAP chemical HAP binds specifically to IL-17A and inhibits the interaction of the cytokine with its receptor, IL-17RA. ABSTRACT
26 32 IL-17A protein HAP binds specifically to IL-17A and inhibits the interaction of the cytokine with its receptor, IL-17RA. ABSTRACT
69 77 cytokine protein_type HAP binds specifically to IL-17A and inhibits the interaction of the cytokine with its receptor, IL-17RA. ABSTRACT
87 95 receptor protein_type HAP binds specifically to IL-17A and inhibits the interaction of the cytokine with its receptor, IL-17RA. ABSTRACT
97 104 IL-17RA protein HAP binds specifically to IL-17A and inhibits the interaction of the cytokine with its receptor, IL-17RA. ABSTRACT
18 23 human species Tested in primary human cells, HAP blocked the production of multiple inflammatory cytokines. ABSTRACT
31 34 HAP chemical Tested in primary human cells, HAP blocked the production of multiple inflammatory cytokines. ABSTRACT
83 92 cytokines protein_type Tested in primary human cells, HAP blocked the production of multiple inflammatory cytokines. ABSTRACT
0 25 Crystal structure studies experimental_method Crystal structure studies revealed that two HAP molecules bind to one IL-17A dimer symmetrically. ABSTRACT
44 47 HAP chemical Crystal structure studies revealed that two HAP molecules bind to one IL-17A dimer symmetrically. ABSTRACT
70 76 IL-17A protein Crystal structure studies revealed that two HAP molecules bind to one IL-17A dimer symmetrically. ABSTRACT
77 82 dimer oligomeric_state Crystal structure studies revealed that two HAP molecules bind to one IL-17A dimer symmetrically. ABSTRACT
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
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
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
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
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
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
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
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
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
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
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
0 6 IL-17A protein IL-17A signals through a specific cell surface receptor complex which consists of IL-17RA and IL-17RC. INTRO
47 55 receptor protein_type IL-17A signals through a specific cell surface receptor complex which consists of IL-17RA and IL-17RC. INTRO
82 89 IL-17RA protein IL-17A signals through a specific cell surface receptor complex which consists of IL-17RA and IL-17RC. INTRO
94 101 IL-17RC protein IL-17A signals through a specific cell surface receptor complex which consists of IL-17RA and IL-17RC. INTRO
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
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
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
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
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
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
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
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
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
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
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
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
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
39 45 IL-17A protein In addition to its physiological role, IL-17A is a key pathogenic factor in inflammatory and autoimmune diseases. INTRO
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
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
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
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
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
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
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
0 11 Secukinumab chemical Secukinumab has been approved recently as a new psoriasis drug by the US Food and Drug Administration (Cosentyx™). INTRO
103 112 Cosentyx™ chemical Secukinumab has been approved recently as a new psoriasis drug by the US Food and Drug Administration (Cosentyx™). INTRO
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
6 21 IL-17 cytokines protein_type Among IL-17 cytokines, IL-17A and IL-17F share the highest homology. INTRO
23 29 IL-17A protein Among IL-17 cytokines, IL-17A and IL-17F share the highest homology. INTRO
34 40 IL-17F protein Among IL-17 cytokines, IL-17A and IL-17F share the highest homology. INTRO
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
18 24 IL-17A protein Identification of IL-17A peptide inhibitors RESULTS
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
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
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
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
0 20 Positive phage pools experimental_method Positive phage pools were then sub-cloned into a maltose-binding protein (MBP) fusion system. RESULTS
31 41 sub-cloned experimental_method Positive phage pools were then sub-cloned into a maltose-binding protein (MBP) fusion system. RESULTS
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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; Table 2). RESULTS
68 73 35–37 chemical C-terminal truncations showed a more gradual reduction in activity (35–37; Table 2). RESULTS
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
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
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
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
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
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
8 17 structure evidence Overall structure of the Fab/IL-17A/HAP complex in ribbon presentation. FIG
25 39 Fab/IL-17A/HAP complex_assembly Overall structure of the Fab/IL-17A/HAP complex in ribbon presentation. FIG
4 7 HAP chemical Two HAP molecules are colored blue and red, and IL-17A monomers are colored ice blue and pink, respectively. FIG
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
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
29 42 binding sites site (A) Overview of the distinct binding sites of Fab and HAP to IL-17A. FIG
46 49 Fab structure_element (A) Overview of the distinct binding sites of Fab and HAP to IL-17A. FIG
54 57 HAP chemical (A) Overview of the distinct binding sites of Fab and HAP to IL-17A. FIG
61 67 IL-17A protein (A) Overview of the distinct binding sites of Fab and HAP to IL-17A. FIG
25 35 IL-17A/HAP complex_assembly (B) Close-in view of the IL-17A/HAP structure. FIG
36 45 structure evidence (B) Close-in view of the IL-17A/HAP structure. FIG
0 6 IL-17A protein IL-17A β-strands are labelled. FIG
7 16 β-strands structure_element IL-17A β-strands are labelled. FIG
16 21 bound protein_state Each of the two bound HAP interacts with both monomers of the IL-17A dimer. FIG
22 25 HAP chemical Each of the two bound HAP interacts with both monomers of the IL-17A dimer. FIG
46 54 monomers oligomeric_state Each of the two bound HAP interacts with both monomers of the IL-17A dimer. FIG
62 68 IL-17A protein Each of the two bound HAP interacts with both monomers of the IL-17A dimer. FIG
69 74 dimer oligomeric_state Each of the two bound HAP interacts with both monomers of the IL-17A dimer. FIG
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
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
21 45 IL-17A/IL-17RA interface site Three distinct areas IL-17A/IL-17RA interface are labeled. FIG
35 49 IL-17A/IL-17RA complex_assembly Mechanism of the inhibition of the IL-17A/IL-17RA interaction by HAP. FIG
65 68 HAP chemical Mechanism of the inhibition of the IL-17A/IL-17RA interaction by HAP. FIG
4 7 HAP chemical (A) HAP binds at region I of IL-17A. FIG
17 25 region I structure_element (A) HAP binds at region I of IL-17A. FIG
29 35 IL-17A protein (A) HAP binds at region I of IL-17A. FIG
0 6 IL-17A protein IL-17A dimer is in surface presentation (β-strands 0 shown as ribbons for clarity). FIG
7 12 dimer oligomeric_state IL-17A dimer is in surface presentation (β-strands 0 shown as ribbons for clarity). FIG
41 52 β-strands 0 structure_element IL-17A dimer is in surface presentation (β-strands 0 shown as ribbons for clarity). FIG
0 18 Polar interactions bond_interaction Polar interactions are shown in dashes. FIG
0 3 HAP chemical HAP residues as well as key IL-17A residues are labeled. FIG
28 34 IL-17A protein HAP residues as well as key IL-17A residues are labeled. FIG
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
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
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
78 81 HAP chemical (B) I-17RA (ribbon in gold) peptide Leu27-Ile32 binds to the same area as the HAP α-helix. FIG
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
0 26 ELISA competition activity experimental_method ELISA competition activity of peptide analogues of 1. TABLE
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