EMD-45983

Single-particle
3.04 Å
EMD-45983 Deposition: 31/07/2024
Map released: 22/01/2025
Last modified: 26/02/2025
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-45983

Native human GABAA receptor of beta2-alpha1-beta3-alpha1-gamma2 assembly

EMD-45983

Single-particle
3.04 Å
EMD-45983 Deposition: 31/07/2024
Map released: 22/01/2025
Last modified: 26/02/2025
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens, Mus musculoides
Sample: Native GABAA receptor purified from human brain
Fitted models: 9cxa (Avg. Q-score: 0.497)

Deposition Authors: Zhou J , Hibbs RE , Noviello CM
Resolving native GABA A receptor structures from the human brain.
Zhou J , Noviello CM , Teng J, Moore H , Lega B , Hibbs RE
(2025) Nature , 638 , 562 - 568
PUBMED: 39843743
DOI: doi:10.1038/s41586-024-08454-1
ISSN: 1476-4687
ASTM: NATUAS
Abstract:
Type A GABA (γ-aminobutyric acid) receptors (GABAA receptors) mediate most fast inhibitory signalling in the brain and are targets for drugs that treat epilepsy, anxiety, depression and insomnia and for anaesthetics1,2. These receptors comprise a complex array of 19 related subunits, which form pentameric ligand-gated ion channels. The composition and structure of native GABAA receptors in the human brain have been inferred from subunit localization in tissue1,3, functional measurements and structural analysis from recombinant expression4-7 and in mice8. However, the arrangements of subunits that co-assemble physiologically in native human GABAA receptors remain unknown. Here we isolated α1 subunit-containing GABAA receptors from human patients with epilepsy. Using cryo-electron microscopy, we defined a set of 12 native subunit assemblies and their 3D structures. We address inconsistencies between previous native and recombinant approaches, and reveal details of previously undefined subunit interfaces. Drug-like densities in a subset of these interfaces led us to uncover unexpected activity on the GABAA receptor of antiepileptic drugs and resulted in localization of one of these drugs to the benzodiazepine-binding site. Proteomics and further structural analysis suggest interactions with the auxiliary subunits neuroligin 2 and GARLH4, which localize and modulate GABAA receptors at inhibitory synapses. This work provides a structural foundation for understanding GABAA receptor signalling and targeted pharmacology in the human brain.