Type-A γ-aminobutyric acid receptors (GABAARs) are the principal mediators of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signalling triggers hyperactive neurological disorders such as insomnia, anxiety and epilepsy. Here we present the first three-dimensional structure of a GABAAR, the human β3 homopentamer, at 3 Å resolution. This structure reveals architectural elements unique to eukaryotic Cys-loop receptors, explains the mechanistic consequences of multiple human disease mutations and shows an unexpected structural role for a conserved N-linked glycan. The receptor was crystallized bound to a previously unknown agonist, benzamidine, opening a new avenue for the rational design of GABAAR modulators. The channel region forms a closed gate at the base of the pore, representative of a desensitized state. These results offer new insights into the signalling mechanisms of pentameric ligand-gated ion channels and enhance current understanding of GABAergic neurotransmission. GABAA receptors are the principal mediators of rapid inhibitor synaptic transmission in the brain, and a decline in GABAA signalling leads to diseases including epilepsy, insomnia, anxiety and autism; here, the first X-ray crystal structure of a human GABAA receptor, the human β3 homopentamer, reveals structural features unique for this receptor class and uncovers the locations of key disease-causing mutations. Paul Miller and Radu Aricescu report the first X-ray crystal structure of the human GABAA receptor, a pentameric ligand-gated ion channel and the principal mediator of rapid inhibitory synaptic transmission in the brain. The overall structure resembles those of other Cys-loop receptors but there are also several unique features, including the presence of an extended glycan sheath that would restrict interactions with other synaptic proteins. The authors discuss how specific mutations may be linked to specific diseases, and since the structure was obtained in the presence of benzamidine, a GABAA receptor agonist, it is hoped that this work could contribute to the design of new therapeutic agents.

Crystal structure of a human GABAA receptor