{"entity": "researcher", "timestamp": "2026-08-20T20:36:29.517Z", "family": "Fan", "given": "Chen", "initials": "C", "orcid": "0000-0003-1211-3427", "affiliations": ["Dept. of Biochemistry and Biophysics, Science for Life Laboratory, Stockholm University, Solna, Sweden."], "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/researcher/8690704777ea45e992b25523219e8b56.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/researcher/8690704777ea45e992b25523219e8b56"}}, "publications": [{"entity": "publication", "iuid": "2c65a482ba864441852de1f61b7ac256", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/2c65a482ba864441852de1f61b7ac256.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/2c65a482ba864441852de1f61b7ac256"}}, "title": "Cryo-EM structures of \u03c11 GABAA receptors with antagonist and agonist drugs.", "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", "orcid": "0000-0002-2734-2794", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/9eb30fa60f9b4b95842ac9d9f3a0eaa9.json"}}], "type": "journal article", "published": "2025-08-01", "journal": {"title": "Nat Commun", "issn": "2041-1723", "volume": "16", "issue": "1", "pages": "7077", "issn-l": "2041-1723"}, "abstract": "The family of \u03c1-type GABAA receptors includes potential therapeutic targets in several neurological conditions, and features distinctive pharmacology compared to other subtypes. Here we report four cryo-EM structures with previously unresolved ligands, electrophysiology recordings, and molecular dynamics simulations to characterize binding and conformational impact of the drugs THIP (a non-opioid analgesic), CGP36742 (a phosphinic acid) and GABOB (an anticonvulsant) on a human \u03c11 GABAA receptor. A distinctive binding pose of THIP in \u03c11 versus \u03b14\u03b23\u03b4 GABAA receptors offers a rationale for its inverse effects on these subtypes. CGP36742 binding is similar to the canonical \u03c1-type inhibitor TPMPA, supporting a shared mechanism of action among phosphinic acids. Binding of GABOB is similar to GABA, but produces a mixture of partially-locked and desensitized states, likely underlying weaker agonist activity. Together, these results elucidate interactions of a \u03c1-type GABAA receptor with therapeutic drugs, offering mechanistic insights and a basis for further pharmaceutical development.", "doi": "10.1038/s41467-025-61932-6", "pmid": "40750757", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC12316911"}, {"db": "pii", "key": "10.1038/s41467-025-61932-6"}], "notes": [], "created": "2026-08-20T08:53:59.682Z", "modified": "2026-08-20T08:53:59.770Z"}, {"entity": "publication", "iuid": "0670bef0a16a4a7b977bd94e2c9d2dad", "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"}, {"entity": "publication", "iuid": "3b7b2b5bd9fe421d99b04ec0d80bee4d", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/3b7b2b5bd9fe421d99b04ec0d80bee4d.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/3b7b2b5bd9fe421d99b04ec0d80bee4d"}}, "title": "Allosteric inhibition of CFTR gating by CFTRinh-172 binding in the pore.", "authors": [{"family": "Gao", "given": "Xiaolong", "initials": "X", "orcid": "0000-0001-8933-9286", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/bee158f76cea46559020da0c706de960.json"}}, {"family": "Yeh", "given": "Han-I", "initials": "HI", "orcid": "0000-0001-5123-6185", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/53f995e5727c4e60ae93d5745740f2fe.json"}}, {"family": "Yang", "given": "Zhengrong", "initials": "Z"}, {"family": "Fan", "given": "Chen", "initials": "C", "orcid": "0000-0003-1211-3427", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/8690704777ea45e992b25523219e8b56.json"}}, {"family": "Jiang", "given": "Fan", "initials": "F"}, {"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": "Kappes", "given": "John C", "initials": "JC"}, {"family": "Hwang", "given": "Tzyh-Chang", "initials": "TC", "orcid": "0000-0002-1967-8167", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/bd89d6a131c14e10a8c4ba941225e607.json"}}], "type": "journal article", "published": "2024-08-06", "journal": {"title": "Nat Commun", "issn": "2041-1723", "volume": "15", "issue": "1", "pages": "6668", "issn-l": "2041-1723"}, "abstract": "Loss-of-function mutations of the CFTR gene cause the life-shortening genetic disease cystic fibrosis (CF), whereas overactivity of CFTR may lead to secretory diarrhea and polycystic kidney disease. While effective drugs targeting the CFTR protein have been developed for the treatment of CF, little progress has been made for diseases caused by hyper-activated CFTR. Here, we solve the cryo-EM structure of CFTR in complex with CFTRinh-172 (Inh-172), a CFTR gating inhibitor with promising potency and efficacy. We find that Inh-172 binds inside the pore of CFTR, interacting with amino acid residues from transmembrane segments (TMs) 1, 6, 8, 9, and 12 through mostly hydrophobic interactions and a salt bridge. Substitution of these residues lowers the apparent affinity of Inh-172. The inhibitor-bound structure reveals re-orientations of the extracellular segment of TMs 1, 8, and 12, supporting an allosteric modulation mechanism involving post-binding conformational changes. This allosteric inhibitory mechanism readily explains our observations that pig CFTR, which preserves all the amino acid residues involved in Inh-172 binding, exhibits a much-reduced sensitivity to Inh-172 and that the apparent affinity of Inh-172 is altered by the CF drug ivacaftor (i.e., VX-770) which enhances CFTR's activity through binding to a site also comprising TM8.", "doi": "10.1038/s41467-024-50641-1", "pmid": "39107303", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC11303713"}, {"db": "pii", "key": "10.1038/s41467-024-50641-1"}], "notes": [], "created": "2026-08-20T08:53:32.601Z", "modified": "2026-08-20T08:53:32.772Z"}, {"entity": "publication", "iuid": "22e99e66ca3b4950995a3ff7ccb172d0", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/22e99e66ca3b4950995a3ff7ccb172d0.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/22e99e66ca3b4950995a3ff7ccb172d0"}}, "title": "Divergent mechanisms of steroid inhibition in the human \u03c11 GABAA receptor", "authors": [{"family": "Lindahl", "given": "Erik", "initials": "E"}, {"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", "initials": "R", "orcid": "0000-0003-2049-3378", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/5ce04593b5b24aaa8978fda1447dd0bf.json"}}], "type": "posted-content", "published": "2024-04-19", "journal": {"issn-l": null}, "abstract": null, "doi": "10.21203/rs.3.rs-4192549/v1", "pmid": null, "labels": [], "xrefs": [], "notes": [], "created": "2026-08-20T12:59:24.839Z", "modified": "2026-08-20T12:59:24.930Z"}, {"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": "0bafc4b8a933469ea95974624d585a3e", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/0bafc4b8a933469ea95974624d585a3e.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/0bafc4b8a933469ea95974624d585a3e"}}, "title": "Structure and dynamics of differential ligand binding in the human \u03c1-type GABA A receptor", "authors": [{"family": "Cowgill", "given": "John", "initials": "J", "orcid": "0000-0002-7968-8359", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/861488d03cd8493388b75eab8476381d.json"}}, {"family": "Fan", "given": "Chen", "initials": "C", "orcid": "0000-0003-1211-3427", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/8690704777ea45e992b25523219e8b56.json"}}, {"family": "Haloi", "given": "Nandan", "initials": "N", "orcid": "0000-0003-3542-333X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/a499486a86ba4df7a27d26dad6222b47.json"}}, {"family": "Tobiasson", "given": "Victor", "initials": "V", "orcid": "0000-0001-8920-017X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/dd671d5261504205a7b50f57e5367cfa.json"}}, {"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": "Lindahl", "given": "Erik", "initials": "E", "orcid": "0000-0002-2734-2794", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/9eb30fa60f9b4b95842ac9d9f3a0eaa9.json"}}], "type": "posted-content", "published": "2023-06-17", "journal": {"issn-l": null}, "abstract": null, "doi": "10.1101/2023.06.16.545288", "pmid": null, "labels": [], "xrefs": [], "notes": [], "created": "2026-08-20T10:46:47.332Z", "modified": "2026-08-20T10:46:47.380Z"}]}