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J Biol Chem. 2017 Feb 3;292(5):1550-1558. doi: 10.1074/jbc.M116.766964. Epub 2016 Dec 16.

Barbiturates Bind in the GLIC Ion Channel Pore and Cause Inhibition by Stabilizing a Closed State.

Author information

1
From the Unité de Dynamique Structurale des Macromolécules, UMR 3528 du CNRS, Institut Pasteur, 75015 Paris, France.
2
the Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom.
3
the UMR 8076 du CNRS, BioCIS, Faculté de Pharmacie, Université Paris Sud, 92296 Chatenay-Malabry, France, and.
4
the Department of Computer Science, University of California, Davis, California 95616.
5
the Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom, t.smart@ucl.ac.uk.
6
From the Unité de Dynamique Structurale des Macromolécules, UMR 3528 du CNRS, Institut Pasteur, 75015 Paris, France, delarue@pasteur.fr.

Abstract

Barbiturates induce anesthesia by modulating the activity of anionic and cationic pentameric ligand-gated ion channels (pLGICs). Despite more than a century of use in clinical practice, the prototypic binding site for this class of drugs within pLGICs is yet to be described. In this study, we present the first X-ray structures of barbiturates bound to GLIC, a cationic prokaryotic pLGIC with excellent structural homology to other relevant channels sensitive to general anesthetics and, as shown here, to barbiturates, at clinically relevant concentrations. Several derivatives of barbiturates containing anomalous scatterers were synthesized, and these derivatives helped us unambiguously identify a unique barbiturate binding site within the central ion channel pore in a closed conformation. In addition, docking calculations around the observed binding site for all three states of the receptor, including a model of the desensitized state, showed that barbiturates preferentially stabilize the closed state. The identification of this pore binding site sheds light on the mechanism of barbiturate inhibition of cationic pLGICs and allows the rationalization of several structural and functional features previously observed for barbiturates.

KEYWORDS:

anesthesia; barbiturates; crystallography; electrophysiology; ligand-gated ion channels; membrane protein; structural biology; x-ray crystallography

PMID:
27986812
PMCID:
PMC5290934
DOI:
10.1074/jbc.M116.766964
[Indexed for MEDLINE]
Free PMC Article

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