Cryo-EM structure of the benzodiazepine-sensitive α1β1γ2S tri-heteromeric GABAA receptor in complex with GABA

Swastik Phulera, Hongtao Zhu, Jie Yu, Derek P. Claxton, Nate Yoder, Craig Yoshioka, Eric Gouaux

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Fast inhibitory neurotransmission in the 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 the profound importance of heteromeric GABAA receptors in neuroscience and medicine, they have proven recalcitrant to structure determination. Here we present the structure of a tri-heteromeric α1β1γEM 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.

Original languageEnglish (US)
Article numbere39383
JournaleLife
Volume7
DOIs
StatePublished - Jul 25 2018

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GABA-A Receptors
Benzodiazepines
gamma-Aminobutyric Acid
Ion Channels
Cysteine Loop Ligand-Gated Ion Channel Receptors
Ion Channel Gating
Glycosylation
Neurology
Neurosciences
Hypnotics and Sedatives
Synaptic Transmission
Anticonvulsants
Nervous System
Medicine
Anesthetics
Chlorides
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Cryo-EM structure of the benzodiazepine-sensitive α1β1γ2S tri-heteromeric GABAA receptor in complex with GABA. / Phulera, Swastik; Zhu, Hongtao; Yu, Jie; Claxton, Derek P.; Yoder, Nate; Yoshioka, Craig; Gouaux, Eric.

In: eLife, Vol. 7, e39383, 25.07.2018.

Research output: Contribution to journalArticle

Phulera, Swastik ; Zhu, Hongtao ; Yu, Jie ; Claxton, Derek P. ; Yoder, Nate ; Yoshioka, Craig ; Gouaux, Eric. / Cryo-EM structure of the benzodiazepine-sensitive α1β1γ2S tri-heteromeric GABAA receptor in complex with GABA. In: eLife. 2018 ; Vol. 7.
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