Cryo-EM structure of the benzodiazepine-sensitive α1β1γ2S tri-heteromeric GABAA receptor in complex with GABA
- Oregon Health and Science University, United States
Abstract
Fast inhibitory neurotransmission in mammalian nervous system is largely mediated by GABAA receptors, chloride-selective members of the superfamily of pentameric Cys-loop receptors. Native GABAA receptors are heteromeric assemblies sensitive to many important drugs, from sedatives to anesthetics and anticonvulsant agents, with mutant forms of GABAA receptors implicated in multiple neurological diseases. Despite profound importance of heteromeric GABAA receptors in neuroscience and medicine, they have proven recalcitrant to structure determination. Here we present the structure of tri-heteromeric α1β1γ2SEM GABAA receptor in complex with GABA, determined by single particle cryo-EM at 3.1-3.8 Å resolution, elucidating molecular principles of receptor assembly and agonist binding. Remarkable N-linked glycosylation on the α1 subunit occludes the extracellular vestibule of the ion channel and is poised to modulate receptor assembly and perhaps ion channel gating. Our work provides a pathway to structural studies of heteromeric GABAA receptors and a framework for rational design of novel therapeutic agents.
Data availability
EM density maps have been deposited to EMDB, the structure of the triheteromeric receptor has been deposited to the PDB
Article and author information
Author details
Funding
National Institute of General Medical Sciences (R01 GM100400)
- Eric Gouaux
Howard Hughes Medical Institute
- Eric Gouaux
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Kenton Jon Swartz, National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States
Version history
- Received: June 20, 2018
- Accepted: July 24, 2018
- Accepted Manuscript published: July 25, 2018 (version 1)
- Version of Record published: August 10, 2018 (version 2)
Copyright
© 2018, Phulera et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Cryo-EM structure of the benzodiazepine-sensitive α1β1γ2S tri-heteromeric GABAA receptor in complex with GABA
eLife 7:e39383.
https://doi.org/10.7554/eLife.39383
