{"entity": "researcher", "timestamp": "2026-08-20T20:45:53.100Z", "family": "Hibbs", "given": "Ryan E", "initials": "RE", "orcid": "0000-0003-4283-1147", "affiliations": ["Departments of Neuroscience and Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. ryan.hibbs@utsouthwestern.edu."], "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/researcher/34cf15e2b34d482f85ffbc4116e8af76.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/researcher/34cf15e2b34d482f85ffbc4116e8af76"}}, "publications": [{"entity": "publication", "iuid": "ef8619f118cf4e2493e7c07b04bc7ebb", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/ef8619f118cf4e2493e7c07b04bc7ebb.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/ef8619f118cf4e2493e7c07b04bc7ebb"}}, "title": "Structural insights into opposing actions of neurosteroids on GABAA receptors.", "authors": [{"family": "Legesse", "given": "Dagimhiwat H", "initials": "DH"}, {"family": "Fan", "given": "Chen", "initials": "C", "orcid": "0000-0003-1211-3427", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/8690704777ea45e992b25523219e8b56.json"}}, {"family": "Teng", "given": "Jinfeng", "initials": "J"}, {"family": "Zhuang", "given": "Yuxuan", "initials": "Y", "orcid": "0000-0003-4390-8556", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/61b8327a0f32416686748c52c38ecbf1.json"}}, {"family": "Howard", "given": "Rebecca J", "initials": "RJ", "orcid": "0000-0003-2049-3378", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/5ce04593b5b24aaa8978fda1447dd0bf.json"}}, {"family": "Noviello", "given": "Colleen M", "initials": "CM"}, {"family": "Lindahl", "given": "Erik", "initials": "E", "orcid": "0000-0002-2734-2794", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/9eb30fa60f9b4b95842ac9d9f3a0eaa9.json"}}, {"family": "Hibbs", "given": "Ryan E", "initials": "RE", "orcid": "0000-0003-4283-1147", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/34cf15e2b34d482f85ffbc4116e8af76.json"}}], "type": "journal article", "published": "2023-08-22", "journal": {"title": "Nat Commun", "issn": "2041-1723", "volume": "14", "issue": "1", "pages": "5091", "issn-l": "2041-1723"}, "abstract": "\u03b3-Aminobutyric acid type A (GABAA) receptors mediate fast inhibitory signaling in the brain and are targets of numerous drugs and endogenous neurosteroids. A subset of neurosteroids are GABAA receptor positive allosteric modulators; one of these, allopregnanolone, is the only drug approved specifically for treating postpartum depression. There is a consensus emerging from structural, physiological and photolabeling studies as to where positive modulators bind, but how they potentiate GABA activation remains unclear. Other neurosteroids are negative modulators of GABAA receptors, but their binding sites remain debated. Here we present structures of a synaptic GABAA receptor bound to allopregnanolone and two inhibitory sulfated neurosteroids. Allopregnanolone binds at the receptor-bilayer interface, in the consensus potentiator site. In contrast, inhibitory neurosteroids bind in the pore. MD simulations and electrophysiology support a mechanism by which allopregnanolone potentiates channel activity and suggest the dominant mechanism for sulfated neurosteroid inhibition is through pore block.", "doi": "10.1038/s41467-023-40800-1", "pmid": "37607940", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC10444788"}, {"db": "pii", "key": "10.1038/s41467-023-40800-1"}], "notes": [], "created": "2026-08-20T08:52:49.376Z", "modified": "2026-08-20T08:52:49.507Z"}, {"entity": "publication", "iuid": "2f7993e94e1742a680b9b7a22eaecb26", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/2f7993e94e1742a680b9b7a22eaecb26.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/2f7993e94e1742a680b9b7a22eaecb26"}}, "title": "Structural and dynamic mechanisms of GABAA receptor modulators with opposing activities.", "authors": [{"family": "Zhu", "given": "Shaotong", "initials": "S"}, {"family": "Sridhar", "given": "Akshay", "initials": "A"}, {"family": "Teng", "given": "Jinfeng", "initials": "J"}, {"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", "orcid": "0000-0002-2734-2794", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/9eb30fa60f9b4b95842ac9d9f3a0eaa9.json"}}, {"family": "Hibbs", "given": "Ryan E", "initials": "RE", "orcid": "0000-0003-4283-1147", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/34cf15e2b34d482f85ffbc4116e8af76.json"}}], "type": "journal article", "published": "2022-08-06", "journal": {"title": "Nat Commun", "issn": "2041-1723", "volume": "13", "issue": "1", "pages": "4582", "issn-l": "2041-1723"}, "abstract": "\u03b3-Aminobutyric acid type A (GABAA) receptors are pentameric ligand-gated ion channels abundant in the central nervous system and are prolific drug targets for treating anxiety, sleep disorders and epilepsy. Diverse small molecules exert a spectrum of effects on \u03b3-aminobutyric acid type A (GABAA) receptors by acting at the classical benzodiazepine site. They can potentiate the response to GABA, attenuate channel activity, or counteract modulation by other ligands. Structural mechanisms underlying the actions of these drugs are not fully understood. Here we present two high-resolution structures of GABAA receptors in complex with zolpidem, a positive allosteric modulator and heavily prescribed hypnotic, and DMCM, a negative allosteric modulator with convulsant and anxiogenic properties. These two drugs share the extracellular benzodiazepine site at the \u03b1/\u03b3 subunit interface and two transmembrane sites at \u03b2/\u03b1 interfaces. Structural analyses reveal a basis for the subtype selectivity of zolpidem that underlies its clinical success. Molecular dynamics simulations provide insight into how DMCM switches from a negative to a positive modulator as a function of binding site occupancy. Together, these findings expand our understanding of how GABAA receptor allosteric modulators acting through a common site can have diverging activities.", "doi": "10.1038/s41467-022-32212-4", "pmid": "35933426", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC9357065"}, {"db": "pii", "key": "10.1038/s41467-022-32212-4"}], "notes": [], "created": "2026-08-20T08:52:02.502Z", "modified": "2026-08-20T08:52:02.589Z"}, {"entity": "publication", "iuid": "ffc9ba01346c418ebd4440c7e8319b50", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/ffc9ba01346c418ebd4440c7e8319b50.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/ffc9ba01346c418ebd4440c7e8319b50"}}, "title": "Differential interactions of resting, activated, and desensitized states of the \u03b17 nicotinic acetylcholine receptor with lipidic modulators", "authors": [{"family": "Zhuang", "given": "Yuxuan", "initials": "Y", "orcid": "0000-0003-4390-8556", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/61b8327a0f32416686748c52c38ecbf1.json"}}, {"family": "Noviello", "given": "Colleen M", "initials": "CM"}, {"family": "Hibbs", "given": "Ryan E", "initials": "RE", "orcid": "0000-0003-4283-1147", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/34cf15e2b34d482f85ffbc4116e8af76.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", "orcid": "0000-0002-2734-2794", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/9eb30fa60f9b4b95842ac9d9f3a0eaa9.json"}}], "type": "posted-content", "published": "2022-04-08", "journal": {"issn-l": null}, "abstract": null, "doi": "10.1101/2022.04.08.487470", "pmid": null, "labels": [], "xrefs": [], "notes": [], "created": "2026-08-20T10:10:52.793Z", "modified": "2026-08-20T10:10:52.868Z"}, {"entity": "publication", "iuid": "5e0f9b133db2489fa93ad28cb03ede3a", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/5e0f9b133db2489fa93ad28cb03ede3a.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/5e0f9b133db2489fa93ad28cb03ede3a"}}, "title": "Shared structural mechanisms of general anaesthetics and benzodiazepines.", "authors": [{"family": "Kim", "given": "Jeong Joo", "initials": "JJ"}, {"family": "Gharpure", "given": "Anant", "initials": "A"}, {"family": "Teng", "given": "Jinfeng", "initials": "J"}, {"family": "Zhuang", "given": "Yuxuan", "initials": "Y", "orcid": "0000-0003-4390-8556", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/61b8327a0f32416686748c52c38ecbf1.json"}}, {"family": "Howard", "given": "Rebecca J", "initials": "RJ", "orcid": "0000-0003-2049-3378", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/5ce04593b5b24aaa8978fda1447dd0bf.json"}}, {"family": "Zhu", "given": "Shaotong", "initials": "S"}, {"family": "Noviello", "given": "Colleen M", "initials": "CM"}, {"family": "Walsh", "given": "Richard M", "initials": "RM", "orcid": "0000-0002-8939-8988", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/b2d4449dfdd54978a0f6341940fc0cdd.json"}}, {"family": "Lindahl", "given": "Erik", "initials": "E"}, {"family": "Hibbs", "given": "Ryan E", "initials": "RE", "orcid": "0000-0003-4283-1147", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/34cf15e2b34d482f85ffbc4116e8af76.json"}}], "type": "journal article", "published": "2020-09-00", "journal": {"title": "Nature", "issn": "1476-4687", "volume": "585", "issue": "7824", "pages": "303-308", "issn-l": "0028-0836"}, "abstract": "Most general anaesthetics and classical benzodiazepine drugs act through positive modulation of \u03b3-aminobutyric acid type A (GABAA) receptors to dampen neuronal activity in the brain1-5. However, direct structural information on the mechanisms of general anaesthetics at their physiological receptor sites is lacking. Here we present cryo-electron microscopy structures of GABAA receptors bound to intravenous anaesthetics, benzodiazepines and inhibitory modulators. These structures were solved in a lipidic environment and are complemented by electrophysiology and molecular dynamics simulations. Structures of GABAA receptors in complex with the anaesthetics phenobarbital, etomidate and propofol reveal both distinct and common transmembrane binding sites, which are shared in part by the benzodiazepine drug diazepam. Structures in which GABAA receptors are bound by benzodiazepine-site ligands identify an additional membrane binding site for diazepam and suggest an allosteric mechanism for anaesthetic reversal by flumazenil. This study provides a foundation for understanding how pharmacologically diverse and clinically essential drugs act through overlapping and distinct mechanisms to potentiate inhibitory signalling in the brain.", "doi": "10.1038/s41586-020-2654-5", "pmid": "32879488", "labels": [], "xrefs": [{"db": "mid", "key": "NIHMS1600184"}, {"db": "pmc", "key": "PMC7486282"}, {"db": "pii", "key": "10.1038/s41586-020-2654-5"}], "notes": [], "created": "2026-08-20T08:56:11.781Z", "modified": "2026-08-20T08:56:11.886Z"}]}