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GABAA receptor signalling mechanisms revealed by structural pharmacology

DOI: 10.1038/s41586-018-0832-5 DOI Help

Authors: Simonas Masiulis (MRC Laboratory of Molecular Biology) , Rooma Desai (Massachusetts General Hospital, Harvard Medical School) , Tomasz Uchanski (Vrije Universiteit Brussel (VUB)) , Itziar Serna Martin (Wellcome Centre for Human Genetics, University of Oxford) , Duncan Laverty (MRC Laboratory of Molecular Biology) , Dimple Karia (Wellcome Centre for Human Genetics, University of Oxford) , Tomas Malinauskas (Wellcome Centre for Human Genetics, University of Oxford) , Jasenko Zivanov (MRC Laboratory of Molecular Biology) , Els Pardon (Vrije Universiteit Brussel (VUB)) , Abhay Kotecha (Thermo Fisher Scientific) , Jan Steyaert (Vrije Universiteit Brussel (VUB)) , Keith W. Miller (Massachusetts General Hospital, Harvard Medical School) , A. Radu Aricescu (MRC Laboratory of Molecular Biology; Wellcome Centre for Human Genetics, University of Oxford)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Nature , VOL 565 , PAGES 454 - 459

State: Published (Approved)
Published: January 2019

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.

Journal Keywords: Cryoelectron microscopy; Ion channels in the nervous system; Ligand-gated ion channels; Receptor pharmacology

Subject Areas: Biology and Bio-materials, Medicine

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