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Crystal structure of a human GABAA receptor

DOI: 10.1038/nature13293 DOI Help
PMID: 24909990 PMID Help

Authors: Paul S. Miller (Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, U.K.) , A. Radu Aricescu (Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, U.K)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature , VOL 512 (7514) , PAGES 270 - 275

State: Published (Approved)
Published: August 2014
Diamond Proposal Number(s): 8423

Open Access Open Access

Abstract: Type-A ?-aminobutyric acid receptors (GABAARs) are the principal mediators of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signalling triggers hyperactive neurological disorders such as insomnia, anxiety and epilepsy. Here we present the first three-dimensional structure of a GABAAR, the human ?3 homopentamer, at 3?Å resolution. This structure reveals architectural elements unique to eukaryotic Cys-loop receptors, explains the mechanistic consequences of multiple human disease mutations and shows an unexpected structural role for a conserved N-linked glycan. The receptor was crystallized bound to a previously unknown agonist, benzamidine, opening a new avenue for the rational design of GABAAR modulators. The channel region forms a closed gate at the base of the pore, representative of a desensitized state. These results offer new insights into the signalling mechanisms of pentameric ligand-gated ion channels and enhance current understanding of GABAergic neurotransmission.

Journal Keywords: Binding; Cell; Conserved; Crystallography ; X-Ray ; Drug; GABA-A; Genetic; Glycosylation ; Humans ; Models ; Molecular ; Mutation ; Polysaccharides ; Protein; Quaternary ; Protein; Tertiary ; Protein; Receptors ; GABA-A ; Synaptic Transmission

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Other Facilities: NO