When Two Become One: Conformational Changes in FXR/RXR Heterodimers Bound to Steroidal Antagonists
Language English Country Germany Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- Keywords
- bile acids, farnesoid X receptor, molecular dynamics simulations, nuclear receptors,
- MeSH
- DNA-Binding Proteins * chemistry MeSH
- Chenodeoxycholic Acid pharmacology MeSH
- Ligands MeSH
- Receptors, Cytoplasmic and Nuclear MeSH
- Transcription Factors * metabolism MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- DNA-Binding Proteins * MeSH
- Chenodeoxycholic Acid MeSH
- Ligands MeSH
- Receptors, Cytoplasmic and Nuclear MeSH
- Transcription Factors * MeSH
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 αAF-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 α5/α6 region, αAF-2, and α9-11. Changes in the heterodimerization interface induced by antagonists seem to be associated with αAF-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.
Faculty of Sciences Charles University Prague Albertov 6 Prague 2 12843 Czechia
PamGene International B 5 Wolvenhoek 10 5211HH 's Hertogenbosch Netherlands
School of Pharmacy Faculty of Health Sciences University of Eastern Finland Kuopio 70211 Finland
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