{"entity": "publication", "iuid": "0670bef0a16a4a7b977bd94e2c9d2dad", "timestamp": "2026-08-20T20:46:03.664Z", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/0670bef0a16a4a7b977bd94e2c9d2dad.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/0670bef0a16a4a7b977bd94e2c9d2dad"}}, "title": "Divergent mechanisms of steroid inhibition in the human \u03c11 GABAA receptor.", "authors": [{"family": "Fan", "given": "Chen", "initials": "C", "orcid": "0000-0003-1211-3427", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/8690704777ea45e992b25523219e8b56.json"}}, {"family": "Cowgill", "given": "John", "initials": "J", "orcid": "0000-0002-7968-8359", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/861488d03cd8493388b75eab8476381d.json"}}, {"family": "Howard", "given": "Rebecca J", "initials": "RJ", "orcid": "0000-0003-2049-3378", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/5ce04593b5b24aaa8978fda1447dd0bf.json"}}, {"family": "Lindahl", "given": "Erik", "initials": "E"}], "type": "journal article", "published": "2024-09-06", "journal": {"title": "Nat Commun", "issn": "2041-1723", "volume": "15", "issue": "1", "pages": "7795", "issn-l": "2041-1723"}, "abstract": "\u03c1-type \u03b3-aminobutyric acid-A (GABAA) receptors are widely distributed in the retina and brain, and are potential drug targets for the treatment of visual, sleep and cognitive disorders. Endogenous neuroactive steroids including \u03b2-estradiol and pregnenolone sulfate negatively modulate the function of \u03c11 GABAA receptors, but their inhibitory mechanisms are not clear. By combining five cryo-EM structures with electrophysiology and molecular dynamics simulations, we characterize binding sites and negative modulation mechanisms of \u03b2-estradiol and pregnenolone sulfate at the human \u03c11 GABAA receptor. \u03b2-estradiol binds in a pocket at the interface between extracellular and transmembrane domains, apparently specific to the \u03c1 subfamily, and disturbs allosteric conformational transitions linking GABA binding to pore opening. In contrast, pregnenolone sulfate binds inside the pore to block ion permeation, with a preference for activated structures. These results illuminate contrasting mechanisms of \u03c11 inhibition by two different neuroactive steroids, with potential implications for subtype-specific gating and pharmacological design.", "doi": "10.1038/s41467-024-51904-7", "pmid": "39242530", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC11379708"}, {"db": "pii", "key": "10.1038/s41467-024-51904-7"}, {"db": "PDB", "key": "8RH4"}, {"db": "PDB", "key": "8RH7"}, {"db": "PDB", "key": "8RH8"}, {"db": "PDB", "key": "8RH9"}, {"db": "PDB", "key": "8RHG"}], "notes": [], "created": "2026-08-20T08:53:36.658Z", "modified": "2026-08-20T08:53:36.735Z"}