A structural perspective on GABAA receptor pharmacology.

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Scott S, Aricescu AR

A structural perspective on GABAA receptor pharmacology.

Curr Opin Struct Biol. 2019 Feb;54:189-197. doi: 10.1016/j.sbi.2019.03.023. Epub 2019 May 23.

PubMed ID
31129381 [ View in PubMed
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Abstract

GABAA receptors are pentameric ligand-gated chloride channels of crucial importance for the vertebrate nervous system physiology. They typically modulate the fast inhibitory neurotransmission, and represent the target receptors for major classes of drugs used in the clinic, such as benzodiazepines and general anesthetics. Recent technological progress in structural biology, in particular single-particle cryo-electron microscopy, has led to fundamental advances in understanding the detailed organization and signalling mechanisms of major GABAA receptor subtypes. This effort culminated with the high-resolution structural analysis of an intact, full-length human heteropentameric receptor, alpha1beta3gamma2, in a lipid bilayer and in complex with small molecule ligands including the commonly used benzodiazepines diazepam (Valium) and alprazolam (Xanax). These structures reveal multiple aspects of receptor activation and provide a path for rational design of subunit-specific GABAA receptor modulators.

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