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

Laverty, D; Thomas, P; Field, M; Andersen, OJ; Gold, MG; Biggin, PC; Gielen, M; (2017) Crystal structures of a GABAA-receptor chimera reveal new endogenous neurosteroid-binding sites. Nature Structural & Molecular Biology , 24 pp. 977-985. 10.1038/nsmb.3477. Green open access

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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.

Type: Article
Title: Crystal structures of a GABAA-receptor chimera reveal new endogenous neurosteroid-binding sites.
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/nsmb.3477
Publisher version: http://dx.doi.org/10.1038/nsmb.3477
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Physiology, Structural biology, X-ray crystallography
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: http://discovery.ucl.ac.uk/id/eprint/10024331
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