Structural Basis for Xenon Inhibition in a Cationic Pentameric Ligand-Gated Ion Channel

PloS One
Ludovic SauguetNathalie Colloc'h

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.

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Citations

Jul 6, 2016·Frontiers in Molecular Neuroscience·Roshan PuthenkalamMargot Ernst
Oct 30, 2016·Proceedings of the National Academy of Sciences of the United States of America·Mieke NysChris Ulens
Dec 31, 2016·Bioinformatics·Matthew Colledge, B A Wallace
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Sep 9, 2017·PloS One·Yvette Véronique Ntsogo EnguénéIsabelle Broutin
Nov 22, 2016·Medical Gas Research·Jacques H AbrainiJean-Jacques Risso
Dec 7, 2019·Journal of Neural Transmission·Déborah Le NoguePatrick Pierre Michel
Dec 10, 2016·The Journal of General Physiology·Shaweta GuptaAnthony Auerbach
Feb 26, 2019·Future Medicinal Chemistry·María Julia AmundarainAlejandro Giorgetti
Jul 13, 2016·Molecular Pharmacology·Carlos F BurgosLuis G Aguayo
Apr 11, 2018·Proceedings of the National Academy of Sciences of the United States of America·Haidai HuMarc Delarue
Dec 18, 2016·The Journal of Biological Chemistry·Zaineb FouratiMarc Delarue
Oct 16, 2019·Journal of Chemical Information and Modeling·D A WinklerI Katz

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Methods Mentioned

BETA
X-ray

Software Mentioned

GLIC
MolProbity
autoBUSTER
CCP4
ELIC

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