Abstract
Computational assessment of the IL-17A structure identified two distinct binding pockets, the β-hairpin pocket and the α-helix pocket. The β-hairpin pocket was hypothesized to be the site of binding for peptide macrocycles. Support for this hypothesis was obtained using HDX-MS which revealed protection to exchange only within the β-hairpin pocket. This data represents the first direct structural evidence of a small molecule binding site on IL-17A that functions to disrupt the interaction with its receptor.
MeSH terms
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Binding Sites / drug effects
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Deuterium Exchange Measurement*
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Dose-Response Relationship, Drug
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Humans
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Interleukin-17 / antagonists & inhibitors*
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Interleukin-17 / metabolism
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Macrocyclic Compounds / chemical synthesis
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Macrocyclic Compounds / chemistry
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Macrocyclic Compounds / pharmacology*
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Mass Spectrometry*
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Models, Molecular
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Molecular Conformation
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Peptides, Cyclic / chemical synthesis
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Peptides, Cyclic / chemistry
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Peptides, Cyclic / pharmacology*
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Structure-Activity Relationship
Substances
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IL17A protein, human
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Interleukin-17
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Macrocyclic Compounds
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Peptides, Cyclic