Work

Cryo-EM structure of the benzodiazepine-sensitive α1β1γ2 heterotrimeric GABA A receptor in complex with GABA illuminates mechanism of receptor assembly and agonist binding

Year: 2018

Type: preprint

Abstract: 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 anticonvulsive agents, with mutant forms of GABA A receptors implicated in multiple neurological diseases, including epilepsy. 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 the triheteromeric α1β1γ2 EM GABA A receptor in complex with GABA, determined by single particle cryo-EM at 3.1-3.8 Å resolution, elucidating the 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 the rational design of novel therapeutic agents.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.1101/337659