GABAA receptor signalling mechanisms revealed by structural pharmacology

Simonas Masiulis (), Rooma Desai, Tomasz Uchański, Itziar Serna Martin, Duncan Laverty, Dimple Karia, Tomas Malinauskas, Jasenko Zivanov, Els Pardon, Abhay Kotecha, Jan Steyaert, Keith W. Miller () and A. Radu Aricescu ()
Additional contact information
Simonas Masiulis: Cambridge Biomedical Campus
Rooma Desai: Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School
Tomasz Uchański: Vrije Universiteit Brussel (VUB)
Itziar Serna Martin: University of Oxford
Duncan Laverty: Cambridge Biomedical Campus
Dimple Karia: University of Oxford
Tomas Malinauskas: University of Oxford
Jasenko Zivanov: Cambridge Biomedical Campus
Els Pardon: Vrije Universiteit Brussel (VUB)
Abhay Kotecha: Thermo Fisher Scientific
Jan Steyaert: Vrije Universiteit Brussel (VUB)
Keith W. Miller: Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School
A. Radu Aricescu: Cambridge Biomedical Campus

Nature, 2019, vol. 565, issue 7740, 454-459

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-018-0832-5

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