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Structural basis for GABAA receptor potentiation by neurosteroids

DOI: 10.1038/nsmb.3484 DOI Help

Authors: Paul S. Miller (University of Oxford) , Suzanne Scott (University of Oxford) , Simonas Masiulis (MRC Laboratory of Molecular Biology) , Luigi De Colibus (University of Oxford) , Els Pardon (VIB-VUB Center for Structural Biology) , Jan Steyaert (VIB-VUB Center for Structural Biology) , A Radu Aricescu (University of Oxford; MRC Laboratory of Molecular Biology)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Structural & Molecular Biology , VOL 90

State: Published (Approved)
Published: October 2017
Diamond Proposal Number(s): 10627

Abstract: Type A γ-aminobutyric acid receptors (GABAARs) are the principal mediators of inhibitory neurotransmission in the human brain. Endogenous neurosteroids interact with GABAARs 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 GABAAR 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 GABAAR 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 GABAARs, a process of broad relevance to pentameric ligand-gated ion channels.

Journal Keywords: Ligand-gated ion channels; X-ray crystallography

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography