Publication Date:
2014-06-10
Description:
Type-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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4167603/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4167603/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Miller, Paul S -- Aricescu, A Radu -- 084655/Wellcome Trust/United Kingdom -- 090532/Wellcome Trust/United Kingdom -- 090532/Z/09/Z/Wellcome Trust/United Kingdom -- G0700232/Medical Research Council/United Kingdom -- MR/L009609/1/Medical Research Council/United Kingdom -- England -- Nature. 2014 Aug 21;512(7514):270-5. doi: 10.1038/nature13293. Epub 2014 Jun 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24909990" target="_blank"〉PubMed〈/a〉
Keywords:
Benzamidines/chemistry/metabolism/pharmacology
;
Binding Sites
;
Cell Membrane/chemistry/metabolism
;
Conserved Sequence
;
Crystallography, X-Ray
;
Drug Design
;
GABA-A Receptor Agonists/chemistry/metabolism/pharmacology
;
Genetic Predisposition to Disease
;
Glycosylation
;
Humans
;
Models, Molecular
;
Mutation/genetics
;
Polysaccharides/chemistry/metabolism
;
Protein Structure, Quaternary
;
Protein Structure, Tertiary
;
Protein Subunits
;
Receptors, GABA-A/*chemistry/genetics
;
Synaptic Transmission
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
