title: Structural Basis for Xenon Inhibition in a Cationic Pentameric Ligand-Gated Ion Channel.
abstract: GLIC receptor is a bacterial pentameric ligand-gated ion channel whose action is inhibited by xenon. Xenon has been used in clinical practice as a potent gaseous anaesthetic for decades, but the molecular mechanism of interactions with its integral membrane receptor targets remains poorly understood. Here we characterize by X-ray crystallography the xenon-binding sites within both the open and "locally-closed" (inactive) conformations of GLIC. Major binding sites of xenon, which differ between the two conformations, were identified in three distinct regions that all belong to the trans-membrane domain of GLIC: 1) in an intra-subunit cavity, 2) at the interface between adjacent subunits, and 3) in the pore. The pore site is unique to the locally-closed form where the binding of xenon effectively seals the channel. A putative mechanism of the inhibition of GLIC by xenon is proposed, which might be extended to other pentameric cationic ligand-gated ion channels.
authors.affiliation: Unité de Dynamique Structurale des Macromolécules (UMR 3528 CNRS) Institut Pasteur, Paris, France.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Sauguet
authors.affiliation: Unité de Dynamique Structurale des Macromolécules (UMR 3528 CNRS) Institut Pasteur, Paris, France.
authors.forename: Zeineb
authors.initials: Z
authors.lastname: Fourati
authors.affiliation: Laboratoire de cristallographie et RMN biologiques (UMR 8015 CNRS), Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Prangé
authors.affiliation: Unité de Dynamique Structurale des Macromolécules (UMR 3528 CNRS) Institut Pasteur, Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Delarue
authors.affiliation: CNRS, UMR 6301, ISTCT CERVOxy group, GIP Cyceron, Caen, France.|UNICAEN, Normandie Univ., UMR 6301 ISTCT, Caen, France.|CEA, DSV/I2BM, UMR 6301 ISTCT, Caen, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Colloc'h
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D000458:Cyanobacteria / Q000737:chemistry* / Q000378:metabolism; D015640:Ion Channel Gating; D007473:Ion Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D014978:Xenon / Q000737:chemistry* / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D007473:Ion Channels; D008024:Ligands; D014978:Xenon