title: Structure of the pentameric ligand-gated ion channel ELIC cocrystallized with its competitive antagonist acetylcholine.
abstract: ELIC, the pentameric ligand-gated ion channel from Erwinia chrysanthemi, is a prototype for Cys-loop receptors. Here we show that acetylcholine is a competitive antagonist for ELIC. We determine the acetylcholine-ELIC cocrystal structure to a 2.9-Å resolution and find that acetylcholine binding to an aromatic cage at the subunit interface induces a significant contraction of loop C and other structural rearrangements in the extracellular domain. The side chain of the pore-lining residue F247 reorients and the pore size consequently enlarges, but the channel remains closed. We attribute the inability of acetylcholine to activate ELIC primarily to weak cation-π and electrostatic interactions in the pocket, because an acetylcholine derivative with a simple quaternary-to-tertiary ammonium substitution activates the channel. This study presents a compelling case for understanding the structural underpinning of the functional relationship between agonism and competitive antagonism in the Cys-loop receptors, providing a new framework for developing novel therapeutic drugs.
authors.affiliation: Department of Anesthesiology, 2057 Biomedical Science Tower 3, 3501 Fifth Avenue, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Pan
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chen
authors.forename: Dan
authors.initials: D
authors.lastname: Willenbring
authors.forename: Ken
authors.initials: K
authors.lastname: Yoshida
authors.forename: Tommy
authors.initials: T
authors.lastname: Tillman
authors.forename: Ossama B
authors.initials: OB
authors.lastname: Kashlan
authors.forename: Aina
authors.initials: A
authors.lastname: Cohen
authors.forename: Xiang-Peng
authors.initials: XP
authors.lastname: Kong
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Pei
authors.initials: P
authors.lastname: Tang
mesh_terms: D000109:Acetylcholine / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D058466:Cysteine Loop Ligand-Gated Ion Channel Receptors / Q000737:chemistry* / Q000378:metabolism; D016974:Dickeya chrysanthemi / Q000737:chemistry* / Q000166:cytology / Q000378:metabolism; D015640:Ion Channel Gating; D058446:Ligand-Gated Ion Channels / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000378:metabolism; D055672:Static Electricity
chemical_list: D058466:Cysteine Loop Ligand-Gated Ion Channel Receptors; D058446:Ligand-Gated Ion Channels; D000644:Quaternary Ammonium Compounds; D000109:Acetylcholine