title: Crystal structure of a human GABAA receptor.
abstract: Type-A γ-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 β3 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.
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Miller
authors.affiliation: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: A Radu
authors.initials: AR
authors.lastname: Aricescu
mesh_terms: D001550:Benzamidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D015195:Drug Design; D058785:GABA-A Receptor Agonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020022:Genetic Predisposition to Disease; D006031:Glycosylation; D006801:Humans; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D011134:Polysaccharides / Q000737:chemistry / Q000378:metabolism; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D021122:Protein Subunits; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000235:genetics; D009435:Synaptic Transmission
chemical_list: D001550:Benzamidines; D058785:GABA-A Receptor Agonists; D011134:Polysaccharides; D021122:Protein Subunits; D011963:Receptors, GABA-A; C032157:benzamidine