Crystal structure of a human GABA(A) receptor

Type-A γ-aminobutyric acid receptors (GABA(A)Rs) are the principal mediators of rapid inhibitory synaptic transmission in the human brain. A decline in GABA(A)R signalling triggers hyperactive neurological disorders such as insomnia, anxiety and epilepsy. Here we present the first three-dimensional structure of a GABA(A)R, 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 a surprising structural role for a conserved N-linked glycan. The receptor was crystallised bound to a previously unknown agonist, benzamidine, opening a new avenue for the rational design of GABA(A)R modulators. The channel region forms a closed gate at the base of the pore, representative of a desensitised state. These results offer new insights into the signalling mechanisms of pentameric ligand-gated ion channels and enhance current understanding of GABAergic neurotransmission.