{"entity": "publication", "iuid": "55c5af5a521f42128556cd27c083bfed", "timestamp": "2026-09-08T10:05:41.386Z", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/55c5af5a521f42128556cd27c083bfed.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/55c5af5a521f42128556cd27c083bfed"}}, "title": "When Two Become One: Conformational Changes in FXR/RXR Heterodimers Bound to Steroidal Antagonists.", "authors": [{"family": "D\u00edaz-Holgu\u00edn", "given": "Alejandro", "initials": "A"}, {"family": "Rashidian", "given": "Azam", "initials": "A"}, {"family": "Pijnenburg", "given": "Dirk", "initials": "D"}, {"family": "Monteiro Ferreira", "given": "Glaucio", "initials": "G"}, {"family": "Stefela", "given": "Alzbeta", "initials": "A"}, {"family": "Kaspar", "given": "Miroslav", "initials": "M"}, {"family": "Kudova", "given": "Eva", "initials": "E"}, {"family": "Poso", "given": "Antti", "initials": "A"}, {"family": "van Beuningen", "given": "Rinie", "initials": "R"}, {"family": "Pavek", "given": "Petr", "initials": "P"}, {"family": "Kronenberger", "given": "Thales", "initials": "T", "orcid": "0000-0001-6933-7590", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/397d07a34a61408c9f2b9e6961c58a31.json"}}], "type": "journal article", "published": "2023-02-14", "journal": {"title": "ChemMedChem", "issn": "1860-7187", "volume": "18", "issue": "4", "pages": "e202200556", "issn-l": "1860-7179"}, "abstract": "Farnesoid X receptor (FXR) is a nuclear receptor with an essential role in regulating bile acid synthesis and cholesterol homeostasis. FXR activation by agonists is explained by an \u03b1AF-2-trapping mechanism; however, antagonism mechanisms are diverse. We discuss microsecond molecular dynamics (MD) simulations investigating our recently reported FXR antagonists 2a and 2 h. We study the antagonist-induced conformational changes in the FXR ligand-binding domain, when compared to the synthetic (GW4064) or steroidal (chenodeoxycholic acid, CDCA) FXR agonists in the FXR monomer or FXR/RXR heterodimer r, and in the presence and absence of the coactivator. Our MD data suggest ligand-specific influence on conformations of different FXR-LBD regions, including the \u03b15/\u03b16 region, \u03b1AF-2, and \u03b19-11. Changes in the heterodimerization interface induced by antagonists seem to be associated with \u03b1AF-2 destabilization, which prevents both co-activator and co-repressor recruitment. Our results provide new insights into the conformational behaviour of FXR, suggesting that FXR antagonism/agonism shift requires a deeper assessment than originally proposed by crystal structures.", "doi": "10.1002/cmdc.202200556", "pmid": "36398403", "labels": [], "xrefs": [], "notes": [], "created": "2026-08-21T11:01:05.013Z", "modified": "2026-08-21T11:01:05.084Z"}