期刊
NATURE
卷 565, 期 7740, 页码 516-+出版社
NATURE RESEARCH
DOI: 10.1038/s41586-018-0833-4
关键词
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资金
- UK Medical Research Council [MR/L009609/1, MC_UP_1201/15, MC_UP_A025_1013]
- UK Biotechnology and Biological Sciences Research Council [BB/M024709/1]
- Human Frontier Science Program [RGP0065/2014]
- Cancer Research UK [C20724/A14414]
- Swiss National Science Foundation [168735]
- National Institute for General Medical Sciences [GM 58448]
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital
- Instruct-ERIC, part of the European Strategy Forum on Research Infrastructures (ESFRI) [PID1271]
- FWO
- BBSRC [BB/M024709/1] Funding Source: UKRI
- MRC [MC_UP_A025_1013, MR/L009609/1, MC_UP_1201/15, MC_EX_MR/L009609/2] Funding Source: UKRI
Type A gamma-aminobutyric acid (GABA(A)) receptors are pentameric ligand-gated ion channels and the main drivers of fast inhibitory neurotransmission in the vertebrate nervous system1,2. Their dysfunction is implicated in a range of neurological disorders, including depression, epilepsy and schizophrenia3,4. Among the numerous assemblies that are theoretically possible, the most prevalent in the brain are the alpha 1 beta 2/3 gamma 2 GABAA receptors5. The beta 3 subunit has an important role in maintaining inhibitory tone, and the expression of this subunit alone is sufficient to rescue inhibitory synaptic transmission in beta 1-beta 3 triple knockout neurons6. So far, efforts to generate accurate structural models for heteromeric GABAA receptors have been hampered by the use of engineered receptors and the presence of detergents7-9. Notably, some recent cryo-electron microscopy reconstructions have reported ` collapsed' conformations8,9; however, these disagree with the structure of the prototypical pentameric ligand-gated ion channel the Torpedo nicotinic acetylcholine receptor10,11, the large body of structural work on homologous homopentameric receptor variants12 and the logic of an ion-channel architecture. Here we present a highresolution cryo-electron microscopy structure of the full-length human alpha 1 beta 3 gamma 2L-a major synaptic GABA(A) receptor isoformthat is functionally reconstituted in lipid nanodiscs. The receptor is bound to a positive allosteric modulator ` megabody' and is in a desensitized conformation. Each GABA(A) receptor pentamer contains two phosphatidylinositol-4,5-bisphosphate molecules, the head groups of which occupy positively charged pockets in the intracellular juxtamembrane regions of a1 subunits. Beyond this level, the intracellular M3-M4 loops are largely disordered, possibly because interacting post-synaptic proteins are not present. This structure illustrates the molecular principles of heteromeric GABA(A) receptor organization and provides a reference framework for future mechanistic investigations of GABAergic signalling and pharmacology.
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