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

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 channels1,2 (pLGICs) such as inhibitory GABAA (γ-aminobutyric acid) receptors and excitatory nicotinic acetylcholine receptors, which are respectively potentiated and inhibited by general anaesthetics. The bacterial homologue from Gloeobacter violaceus3 (GLIC), whose X-ray structure was recently solved4,5, is also sensitive to clinical concentrations of general anaesthetics6. 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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Figure 1: Propofol and desflurane binding sites.
Figure 2: Residues of the binding site.
Figure 3: Electrophysiological characterization of binding-site residues.
Figure 4: Molecular dynamics simulation of propofol bound to GLIC.

Accession codes

Primary accessions

Protein Data Bank

Data deposits

The coordinates of models are deposited in Protein Data Bank under accession numbers 3P50 (propofol) and 3P4W (desflurane).

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Acknowledgements

This work was supported by the Commission of the European Communities (Neurocypres project; to H.N.), the Louis D. Foundation of the Institut de France, the Network of European Neuroscience Institutes (ENI-NET) and a National Institutes of Health grant NIGMS R01 GM069379 (to J.M.S.). We thank J. Brallet for the gift of desflurane, the European Synchrotron Radiation Facility and Soleil staff for assistance during data collection, and G. Brannigan for providing propofol simulation parameters. Simulations were performed using high-performance computing resources from the Grand Equipement National de Calcul Intensif, Institut du Développement et des Ressources en Informatique Scientifique (GENCI-IDRIS, grant 2009-072292).

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Correspondence to Marc Delarue or Pierre-Jean Corringer.

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Nury, H., Van Renterghem, C., Weng, Y. et al. X-ray structures of general anaesthetics bound to a pentameric ligand-gated ion channel. Nature 469, 428–431 (2011). https://doi.org/10.1038/nature09647

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