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

eLife

Craig Yoshioka¹  Hongtao Zhu¹  Derek P Claxton¹  Swastik Phulera¹  Jie Yu¹  Nate Yoder¹  Eric Gouaux¹ 

[1] Vollum Institute, Oregon Health and Science University, Portland, United States;

关键词: neurotransmission;    GABA receptors;    cryo-electron microscopy;    GABA;    Cys loop receptors;    ion channel;   

DOI  :  10.7554/eLife.39383

来源: DOAJ

【 摘 要 】

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 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.

【 授权许可】

Unknown