title: Structure of the pentameric ligand-gated ion channel GLIC bound with anesthetic ketamine.
abstract: Pentameric ligand-gated ion channels (pLGICs) are targets of general anesthetics, but a structural understanding of anesthetic action on pLGICs remains elusive. GLIC, a prokaryotic pLGIC, can be inhibited by anesthetics, including ketamine. The ketamine concentration leading to half-maximal inhibition of GLIC (58 μM) is comparable to that on neuronal nicotinic acetylcholine receptors. A 2.99 Å resolution X-ray structure of GLIC bound with ketamine revealed ketamine binding to an intersubunit cavity that partially overlaps with the homologous antagonist-binding site in pLGICs. The functional relevance of the identified ketamine site was highlighted by profound changes in GLIC activation upon cysteine substitution of the cavity-lining residue N152. The relevance is also evidenced by changes in ketamine inhibition upon the subsequent chemical labeling of N152C. The results provide structural insight into the molecular recognition of ketamine and are valuable for understanding the actions of anesthetics and other allosteric modulators on pLGICs.
authors.affiliation: Department of Anesthesiology, Biomedical Science Tower 3, 3501 Fifth Avenue, University of Pittsburgh School of Medicine, Pittsburgh, PA 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: David
authors.initials: D
authors.lastname: Mowrey
authors.forename: Xiang-Peng
authors.initials: XP
authors.lastname: Kong
authors.forename: Aina
authors.initials: A
authors.lastname: Cohen
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Divito
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Pei
authors.initials: P
authors.lastname: Tang
mesh_terms: D000778:Anesthetics, Dissociative / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000737:chemistry*; D001665:Binding Sites; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D000458:Cyanobacteria; D006863:Hydrogen-Ion Concentration; D007649:Ketamine / Q000737:chemistry* / Q000494:pharmacology; D058446:Ligand-Gated Ion Channels / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000737:chemistry*; D008958:Models, Molecular; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D014981:Xenopus
chemical_list: D000778:Anesthetics, Dissociative; D001426:Bacterial Proteins; D058446:Ligand-Gated Ion Channels; D007649:Ketamine