{"entity": "publication", "iuid": "6062c00d27234988b3866700c5ed19b3", "timestamp": "2026-11-06T06:00:43.813Z", "links": {"self": {"href": "https://publications.scilifelab.se/publication/6062c00d27234988b3866700c5ed19b3.json"}, "display": {"href": "https://publications.scilifelab.se/publication/6062c00d27234988b3866700c5ed19b3"}}, "title": "Structural basis for activation and potentiation in a human \u03b15\u03b23 GABAA receptor.", "authors": [{"family": "Cowgill", "given": "John", "initials": "J", "orcid": "0000-0002-7968-8359", "researcher": {"href": "https://publications.scilifelab.se/researcher/b126d68c2326490cba52c41660102eab.json"}}, {"family": "Fan", "given": "Chen", "initials": "C", "orcid": "0000-0003-1211-3427", "researcher": {"href": "https://publications.scilifelab.se/researcher/93fd91b8976642a988e6d522b255e693.json"}}, {"family": "Steyaert", "given": "Jan", "initials": "J", "orcid": "0000-0002-3825-874X", "researcher": {"href": "https://publications.scilifelab.se/researcher/2a13eb5511e1448fb982b5bd1bb1d6f1.json"}}, {"family": "Howard", "given": "Rebecca J", "initials": "RJ", "orcid": "0000-0003-2049-3378", "researcher": {"href": "https://publications.scilifelab.se/researcher/38df565fa7a14daf8c3820579c704ad2.json"}}, {"family": "Lindahl", "given": "Erik", "initials": "E", "orcid": "0000-0002-2734-2794", "researcher": {"href": "https://publications.scilifelab.se/researcher/4f3c67b3b2b84170818b4799725620c5.json"}}], "type": "journal article", "published": "2026-06-15", "journal": {"title": "Nat Commun", "issn": "2041-1723", "volume": "17", "issue": "1", "issn-l": "2041-1723"}, "abstract": "Anesthetics and anticonvulsants act, in part, through diverse populations of type-A \u0263-aminobutyric acid receptors (GABAARs) formed from a pool of 19 subunits. In the hippocampus, \u03b15 subunits primarily coassemble with \u03b23 and, in some cases, \u03b32, generating numerous subtypes with differential functional and pharmacological properties critical in learning and memory. The stoichiometry, structure, and gating of these subpopulations are poorly understood. Here we show using cryogenic electron microscopy and electrophysiology that the human \u03b15\u03b23 GABAAR predominantly assembles with 2\u03b1:3\u03b2 stoichiometry, though a minority population of 1\u03b1:4\u03b2 indicates multiple assemblies are possible. In a resting-like state, a conserved activation gate and Zn2+-coordination at histidines on \u03b23 block ion conduction. Upon GABA binding, global rearrangements release Zn2+ and open the activation gate in nearly all receptors. The activated receptor is unaffected upon binding the anesthetic etomidate or anticonvulsant topiramate, supporting a conformational selection mechanism of action. This work thus reveals the assembly, activation, and modulation of a GABAAR subtype critical to cognition, providing templates for structure-based drug discovery.", "doi": "10.1038/s41467-026-74279-3", "pmid": "42297817", "labels": {"Cryo-EM": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC13269941"}, {"db": "pii", "key": "10.1038/s41467-026-74279-3"}], "notes": [], "created": "2026-11-05T15:02:34.878Z", "modified": "2026-11-05T15:02:35.081Z"}