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TitleCryo-EM structure of the benzodiazepine-sensitive α1β1γ2S tri-heteromeric GABA receptor in complex with GABA.
Journal, issue, pagesElife, Vol. 7, Year 2018
Publish dateJul 25, 2018
AuthorsSwastik Phulera / Hongtao Zhu / Jie Yu / Derek P Claxton / Nate Yoder / Craig Yoshioka / Eric Gouaux /
PubMed AbstractFast inhibitory neurotransmission in the mammalian nervous system is largely mediated by GABA receptors, chloride-selective members of the superfamily of pentameric Cys-loop receptors. Native GABA ...Fast inhibitory neurotransmission in the mammalian nervous system is largely mediated by GABA receptors, chloride-selective members of the superfamily of pentameric Cys-loop receptors. Native GABA receptors are heteromeric assemblies sensitive to many important drugs, from sedatives to anesthetics and anticonvulsant agents, with mutant forms of GABA receptors implicated in multiple neurological diseases. Despite the profound importance of heteromeric GABA receptors in neuroscience and medicine, they have proven recalcitrant to structure determination. Here we present the structure of a tri-heteromeric α1β1γ2S GABA 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 GABA receptors and a framework for rational design of novel therapeutic agents.
External linksElife / PubMed:30044221 / PubMed Central
MethodsEM (single particle)
Resolution3.1 - 3.8 Å
Structure data

8922

6dw0

EMDB-8922: Cryo-EM structure of the benzodiazepine-sensitive alpha1-beta1-gamma2 heterotrimeric GABAA receptor in complex with GABA
PDB-6dw0: Cryo-EM structure of the benzodiazepine-sensitive alpha1beta1gamma2S tri-heteromeric GABAA receptor in complex with GABA (Whole map)
Method: EM (single particle) / Resolution: 3.8 Å

8923

6dw1

EMDB-8923: Cryo-EM structure of the benzodiazepine-sensitive alpha1-beta1-gamma2 heterotrimeric GABAA receptor in complex with GABA
PDB-6dw1: Cryo-EM structure of the benzodiazepine-sensitive alpha1beta1gamma2S tri-heteromeric GABAA receptor in complex with GABA (ECD map)
Method: EM (single particle) / Resolution: 3.1 Å

Chemicals

ChemComp-ABU:
GAMMA-AMINO-BUTANOIC ACID / neurotransmitter, inhibitor*YM / Γ-Aminobutyric acid

Source
  • rattus norvegicus (Norway rat)
KeywordsMEMBRANE PROTEIN / Neurotransmission / GABA Receptors / GABA / Cys Loop Receptors / Ion Channel

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