title: A Binding Site on IL-17A for Inhibitory Macrocycles Revealed by Hydrogen/Deuterium Exchange Mass Spectrometry.
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.
authors: Centro de Investigación Lilly, SA , Avenida de la Industria 30, 28108 Alcobendas, Spain.
authors: Alfonso
authors: A
authors: Espada
authors: Centro de Investigación Lilly, SA , Avenida de la Industria 30, 28108 Alcobendas, Spain.
authors: Howard
authors: H
authors: Broughton
authors: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
authors: Spencer
authors: S
authors: Jones
authors: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
authors: Michael J
authors: MJ
authors: Chalmers
authors: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
authors: Jeffrey A
authors: JA
authors: Dodge
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D041961:Deuterium Exchange Measurement; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013058:Mass Spectrometry; D008958:Models, Molecular; D008968:Molecular Conformation; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C508717:IL17A protein, human; D020381:Interleukin-17; D047028:Macrocyclic Compounds; D010456:Peptides, Cyclic