GABAA receptor signalling mechanisms revealed by structural pharmacology
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Masiulis, Simonas
Desai, Rooma
Uchański, Tomasz
Serna Martin, Itziar
Laverty, Duncan
Karia, Dimple
Malinauskas, Tomas
Zivanov, Jasenko
Pardon, Els
Kotecha, Abhay
Steyaert, Jan
Aricescu, A. Radu
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https://doi.org/10.1038/s41586-018-0832-5Metadata
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Masiulis, Simonas, Rooma Desai, Tomasz Uchański, Itziar Serna Martin, Duncan Laverty, Dimple Karia, Tomas Malinauskas et al. "GABAA receptor signalling mechanisms revealed by structural pharmacology." Nature 565;7740 (2019): 454-459. DOI: 10.1038/s41586-018-0832-5Abstract
Type-A -aminobutyric receptors (GABAARs) 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 common substances of abuse. Without reliable structural data, the mechanistic basis for pharmacological modulation of GABAARs remains largely unknown. Here we report high-resolution cryoEM structures of the full-length human 132L GABAAR in lipid nanodiscs, bound to the channel blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA and the classical benzodiazepines alprazolam (Xanax) and diazepam (Valium), respectively. We describe the binding modes and mechanistic impacts of these ligands, the closed and desensitised states of the GABAAR gating cycle, and the basis for allosteric coupling between the extracellular, agonist-binding, and the transmembrane, pore-forming, regions. This work provides a structural framework to integrate decades of physiology and pharmacology research and a rational basis for development of novel GABAAR modulators.Citable link to this page
https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37373063
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