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Cryo-EM structure of the benzodiazepine-sensitive ?1?1?2S tri-heteromeric GABAA receptor in complex with GABA.


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 ?1?1?2SEM 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 ?1 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.

SUBMITTER: Phulera S 

PROVIDER: S-EPMC6086659 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Cryo-EM structure of the benzodiazepine-sensitive α1β1γ2S tri-heteromeric GABA<sub>A</sub> receptor in complex with GABA.

Phulera Swastik S   Zhu Hongtao H   Yu Jie J   Claxton Derek P DP   Yoder Nate N   Yoshioka Craig C   Gouaux Eric E  

eLife 20180725


Fast inhibitory neurotransmission in the mammalian nervous system is largely mediated by GABA<sub>A</sub> receptors, chloride-selective members of the superfamily of pentameric Cys-loop receptors. Native GABA<sub>A</sub> receptors are heteromeric assemblies sensitive to many important drugs, from sedatives to anesthetics and anticonvulsant agents, with mutant forms of GABA<sub>A</sub> receptors implicated in multiple neurological diseases. Despite the profound importance of heteromeric GABA<sub>  ...[more]

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