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Crystal structure of a human gamma-aminobutyric acid receptor, the GABA(A)R-beta3 homopentamerCrystal structure of a human gamma-aminobutyric acid receptor, the GABA(A)R-beta3 homopentamer
Structural highlights
DiseaseGBRB3_HUMAN Autism;Childhood absence epilepsy. Disease susceptibility is associated with variations affecting the gene represented in this entry. FunctionGBRB3_HUMAN GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel. Publication Abstract from PubMedType-A gamma-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 beta3 homopentamer, at 3 A 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. Crystal structure of a human GABA receptor.,Miller PS, Aricescu AR Nature. 2014 Jun 8. doi: 10.1038/nature13293. PMID:24909990[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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