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Crystal structures of a GABAA-receptor chimera reveal new endogenous neurosteroid-binding sites
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
Discipline Tags:
Health & Wellbeing
Neurology
Structural biology
Drug Discovery
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)