Journal
NATURE
Volume 512, Issue 7514, Pages 270-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature13293
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Funding
- Wellcome Trust (OXION: Ion channels and Disease Initiative) [084655]
- UK Medical Research Council ((MRC)) [G0700232]
- Royal Society [RG090810]
- Wellcome Trust [090532/Z/09/Z]
- MRC [G0700232, MR/L009609/1] Funding Source: UKRI
- Medical Research Council [MR/L009609/1, G0700232] Funding Source: researchfish
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Type-A gamma-aminobutyric acid receptors (GABA(A)Rs) are the principal mediators of rapid inhibitory synaptic transmission in the human brain. A decline in GABA(A)R signalling triggers hyperactive neurological disorders such as insomnia, anxiety and epilepsy. Here we present the first three-dimensional structure of a GABA(A)R, the human beta 3homopentamer, at 3 angstrom 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 GABA(A)R 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.
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