Crystal structures of a GABAA-receptor chimera reveal new endogenous neurosteroid-binding sites

DOI: 10.1038/nsmb.3477

Authors: Duncan Laverty (University College London) , Philip Thomas (University College London) , Martin Field (University College London (UCL)) , Ole J. Andersen (University of Oxford) , Matthew G. Gold (University College London (UCL)) , Philip C. Biggin (University of Oxford) , Marc Gielen (University College London) , Trevor G. Smart (University College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Structural & Molecular Biology , VOL 22

State: Published (Approved)
Published: October 2017
Diamond Proposal Number(s): 12305

Abstract: γ-Aminobutyric acid receptors (GABAARs) are vital for controlling excitability in the brain. This is emphasized by the numerous neuropsychiatric disorders that result from receptor dysfunction. A critical component of most native GABAARs is the α subunit. Its transmembrane domain is the target for many modulators, including endogenous brain neurosteroids that impact anxiety, stress and depression, and for therapeutic drugs, such as general anesthetics. Understanding the basis for the modulation of GABAAR function requires high-resolution structures. Here we present the first atomic structures of a GABAAR chimera at 2.8-Å resolution, including those bound with potentiating and inhibitory neurosteroids. These structures define new allosteric binding sites for these modulators that are associated with the α-subunit transmembrane domain. Our findings will enable the exploitation of neurosteroids for therapeutic drug design to regulate GABAARs in neurological disorders.

Journal Keywords: Physiology; Structural biology; X-ray crystallography

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Other Facilities: ESRF

Added On: 11/10/2017 10:46

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