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Nature. 2019 Jan 2. doi: 10.1038/s41586-018-0833-4. [Epub ahead of print]

Cryo-EM structure of the human α1β3γ2 GABAA receptor in a lipid bilayer.

Author information

1
MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, UK. dlaverty@mrc-lmb.cam.ac.uk.
2
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
3
Structural Biology Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
4
VIB-VUB Center for Structural Biology, VIB, Brussels, Belgium.
5
MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, UK.
6
Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
7
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. kwmiller@mgh.harvard.edu.
8
MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, UK. radu@mrc-lmb.cam.ac.uk.
9
Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK. radu@mrc-lmb.cam.ac.uk.

Abstract

Type A γ-aminobutyric acid (GABAA) 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 α1β2/3γ2 GABAA receptors5. The β3 subunit has an important role in maintaining inhibitory tone, and the expression of this subunit alone is sufficient to rescue inhibitory synaptic transmission in β1-β3 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 high-resolution cryo-electron microscopy structure of the full-length human α1β3γ2L-a major synaptic GABAA receptor isoform-that is functionally reconstituted in lipid nanodiscs. The receptor is bound to a positive allosteric modulator 'megabody' and is in a desensitized conformation. Each GABAA receptor pentamer contains two phosphatidylinositol-4,5-bisphosphate molecules, the head groups of which occupy positively charged pockets in the intracellular juxtamembrane regions of α1 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 GABAA receptor organization and provides a reference framework for future mechanistic investigations of GABAergic signalling and pharmacology.

PMID:
30602789
DOI:
10.1038/s41586-018-0833-4

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