Structure of a human synaptic GABA A receptor

• Published in: Nature (London) Vol. 559; no. 7712; pp. 67 - 72
• Main Authors: Zhu, Shaotong, Noviello, Colleen M, Teng, Jinfeng, Walsh, Jr, Richard M, Kim, Jeong Joo, Hibbs, Ryan E
• Format: Journal Article
• Language: English
• Published: England 05-07-2018
• Subjects: Benzodiazepines - antagonists & inhibitors; Benzodiazepines - chemistry; Benzodiazepines - metabolism; Benzodiazepines - pharmacology; Bicuculline - pharmacology; Binding, Competitive - drug effects; Brain Chemistry; Cell Membrane - chemistry; Cell Membrane - metabolism; Cryoelectron Microscopy; Flumazenil - chemistry; Flumazenil - metabolism; Flumazenil - pharmacology; GABA Modulators - chemistry; GABA Modulators - metabolism; GABA Modulators - pharmacology; gamma-Aminobutyric Acid - chemistry; gamma-Aminobutyric Acid - metabolism; gamma-Aminobutyric Acid - pharmacology; Glycosylation; HEK293 Cells; Humans; Immunoglobulin Fab Fragments - chemistry; Immunoglobulin Fab Fragments - immunology; Ligands; Models, Molecular; Receptors, GABA-A - chemistry; Receptors, GABA-A - immunology; Receptors, GABA-A - metabolism; Receptors, GABA-A - ultrastructure
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-018-0255-3

Fast inhibitory neurotransmission in the brain is principally mediated by the neurotransmitter GABA (γ-aminobutyric acid) and its synaptic target, the type A GABA receptor (GABA
receptor). Dysfunction of this receptor results in neurological disorders and mental illnesses including epilepsy, anxiety and insomnia. The GABA
receptor is also a prolific target for therapeutic, illicit and recreational drugs, including benzodiazepines, barbiturates, anaesthetics and ethanol. Here we present high-resolution cryo-electron microscopy structures of the human α1β2γ2 GABA
receptor, the predominant isoform in the adult brain, in complex with GABA and the benzodiazepine site antagonist flumazenil, the first-line clinical treatment for benzodiazepine overdose. The receptor architecture reveals unique heteromeric interactions for this important class of inhibitory neurotransmitter receptor. This work provides a template for understanding receptor modulation by GABA and benzodiazepines, and will assist rational approaches to therapeutic targeting of this receptor for neurological disorders and mental illness.