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Nature. 2019 Jan 2. doi: 10.1038/s41586-018-0832-5. [Epub ahead of print]

GABAA receptor signalling mechanisms revealed by structural pharmacology.

Author information

1
MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, UK. simonasm@mrc-lmb.cam.ac.uk.
2
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
3
Structural Biology Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
4
VIB-VUB Center for Structural Biology, VIB, Brussels, Belgium.
5
Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
6
MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, UK.
7
Materials and Structural Analysis, Thermo Fisher Scientific, Eindhoven, The Netherlands.
8
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. kwmiller@mgh.harvard.edu.
9
MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, UK. radu@mrc-lmb.cam.ac.uk.
10
Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK. radu@mrc-lmb.cam.ac.uk.

Abstract

Type-A γ-aminobutyric (GABAA) receptors are ligand-gated chloride channels with a very rich pharmacology. Some of their modulators, including benzodiazepines and general anaesthetics, are among the most successful drugs in clinical use and are common substances of abuse. Without reliable structural data, the mechanistic basis for the pharmacological modulation of GABAA receptors remains largely unknown. Here we report several high-resolution cryo-electron microscopy structures in which the full-length human α1β3γ2L GABAA receptor in lipid nanodiscs is bound to the channel-blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA (γ-aminobutyric acid), and the classical benzodiazepines alprazolam and diazepam. We describe the binding modes and mechanistic effects of these ligands, the closed and desensitized states of the GABAA receptor gating cycle, and the basis for allosteric coupling between the extracellular, agonist-binding region and the transmembrane, pore-forming region. This work provides a structural framework in which to integrate previous physiology and pharmacology research and a rational basis for the development of GABAA receptor modulators.

PMID:
30602790
DOI:
10.1038/s41586-018-0832-5

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