Cited by 412Nicotinic Acetylcholine Receptors StudyAnesthesia and Sedative AgentsNeuroscience and Neuropharmacology Research

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X-ray structures of general anaesthetics bound to a pentameric ligand-gated ion channel

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Nury, Hugues, Van Renterghem, Catherine, Weng, Yun, Tran, Alphonso, Baaden, Marc, Dufresne, Virginie, Changeux, Jean-Pierre, Sonner, James M., Delarue, Marc, Corringer, Pierre-Jean·2011·Nature

DOI 10.1038/nature09647

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Abstract

General anaesthetics have enjoyed long and widespread use but their molecular mechanism of action remains poorly understood. There is good evidence that their principal targets are pentameric ligand-gated ion channels (pLGICs) such as inhibitory GABA(A) (γ-aminobutyric acid) receptors and excitatory nicotinic acetylcholine receptors, which are respectively potentiated and inhibited by general anaesthetics. The bacterial homologue from Gloeobacter violaceus (GLIC), whose X-ray structure was recently solved, is also sensitive to clinical concentrations of general anaesthetics. Here we describe the crystal structures of the complexes propofol/GLIC and desflurane/GLIC. These reveal a common general-anaesthetic binding site, which pre-exists in the apo-structure in the upper part of the transmembrane domain of each protomer. Both molecules establish van der Waals interactions with the protein; propofol binds at the entrance of the cavity whereas the smaller, more flexible, desflurane binds deeper inside. Mutations of some amino acids lining the binding site profoundly alter the ionic response of GLIC to protons, and affect its general-anaesthetic pharmacology. Molecular dynamics simulations, performed on the wild type (WT) and two GLIC mutants, highlight differences in mobility of propofol in its binding site and help to explain these effects. These data provide a novel structural framework for the design of general anaesthetics and of allosteric modulators of brain pLGICs.

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Authors: Nury, H., Van Renterghem, C., Weng, Y., Tran, A., Baaden, M., Dufresne, V., Changeux, J.-P., Sonner, J. M., Delarue, M., & Corringer, P.-J.
Affiliations: Institut Pasteur (FR)
University of California, San Francisco (US)
Centre National de la Recherche Scientifique (FR)
Corresponding author: Changeux, Jean-Pierre
Delarue, Marc
Corringer, Pierre-Jean
ORCID: Nury, Hugues
Baaden, Marc
Changeux, Jean-Pierre
Delarue, Marc
Corringer, Pierre-Jean
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2011-01
Volume: 469
Issue: 7330
Pages: 428-431
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature09647
OpenAlex: W2104389482
Cited by: 412
References: 48
Citations by year: 2026: 5 · 2025: 2 · 2024: 8 · 2023: 8 · 2022: 8 · 2021: 23 · 2020: 18 · 2019: 21 · 2018: 28 · 2017: 32 · 2016: 33 · 2015: 34 · 2014: 36 · 2013: 62 · 2012: 56
FWCI: 25.08
Type: journal article
Language: en
Open access: green
infoscience.epfl.ch
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
HAL (submittedVersion)
RePEc: Research Papers in Economics (submittedVersion)
eScholarship (California Digital Library) (submittedVersion)
Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
Funders: National Institute of General Medical Sciences (R01GM069379)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
Health Sciences › Medicine › Anesthesiology and Pain Medicine › Anesthesia and Sedative Agents
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: general anesthetics, pentameric ligand-gated ion channels, propofol, desflurane, transmembrane domain, allosteric modulators, proton sensitivity, molecular dynamics simulation, GABAA receptor, nicotinic acetylcholine receptors
MeSH terms: Desflurane, Cyanobacteria, Binding Sites, Isoflurane, Ligands, Models, Molecular, Protein Binding, Protons, Propofol, Protein Structure, Tertiary, Crystallography, X-Ray, Anesthetics, General, Mutant Proteins, Electrophysiological Phenomena, Molecular Dynamics Simulation, Ligand-Gated Ion Channels

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X-ray structures of general anaesthetics bound to a pentameric ligand-gated ion channel

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