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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.

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