Download MendeleyCryo-EM structure of the benzodiazepine-sensitive alpha 1 beta 1 gamma 2S tri-heteromeric GABAAreceptor in complex with GABA.
Phulera, S., Zhu, H., Yu, J., Claxton, D.P., Yoder, N., Yoshioka, C., Gouaux, E.(2018) Elife 7
- PubMed: 30044221
- DOI: https://doi.org/10.7554/eLife.39383
- Primary Citation of Related Structures:
6DW0, 6DW1 - PubMed Abstract:
Fast inhibitory neurotransmission in the mammalian nervous system is largely mediated by GABA A receptors, chloride-selective members of the superfamily of pentameric Cys-loop receptors. Native GABA A receptors are heteromeric assemblies sensitive to many important drugs, from sedatives to anesthetics and anticonvulsant agents, with mutant forms of GABA A receptors implicated in multiple neurological diseases. Despite the profound importance of heteromeric GABA A receptors in neuroscience and medicine, they have proven recalcitrant to structure determination. Here we present the structure of a tri-heteromeric α1β1γ2S EM GABA A 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 A receptors and a framework for rational design of novel therapeutic agents.
Organizational Affiliation:
Vollum Institute, Oregon Health and Science University, Portland, United States.
