Structural basis for GABA receptor potentiation by neurosteroids.

TitleStructural basis for GABA receptor potentiation by neurosteroids.
Publication TypeJournal Article
Year of Publication2017
AuthorsMiller, P. S., S. Scott, S. Masiulis, L. De Colibus, E. Pardon, J. Steyaert, and R. A Aricescu
JournalNat Struct Mol Biol
Date Published2017 Nov
KeywordsCrystallography, X-Ray, Humans, Models, Molecular, Neurotransmitter Agents, Protein Binding, Protein Conformation, Receptors, GABA-A

Type A γ-aminobutyric acid receptors (GABARs) are the principal mediators of inhibitory neurotransmission in the human brain. Endogenous neurosteroids interact with GABARs to regulate acute and chronic anxiety and are potent sedative, analgesic, anticonvulsant and anesthetic agents. Their mode of binding and mechanism of receptor potentiation, however, remain unknown. Here we report crystal structures of a chimeric GABAR construct in apo and pregnanolone-bound states. The neurosteroid-binding site is mechanically coupled to the helices lining the ion channel pore and modulates the desensitization-gate conformation. We demonstrate that the equivalent site is responsible for physiological, heteromeric GABAR potentiation and explain the contrasting modulatory properties of 3a versus 3b neurosteroid epimers. These results illustrate how peripheral lipid ligands can regulate the desensitization gate of GABARs, a process of broad relevance to pentameric ligand-gated ion channels.

Alternate JournalNat. Struct. Mol. Biol.
PubMed ID28991263
Grant ListMR/L009609/1 / / Medical Research Council / United Kingdom
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