When Two Become One: Conformational Changes in FXR/RXR Heterodimers Bound to Steroidal Antagonists

Author(s):Show less -

Diaz-Holguin, Alejandro ; Rashidian, Azam ; Pijnenburg, Dirk ; Monteiro Ferreira, Glaucio ; Stefela, Alzbeta ; Kaspar, Miroslav ; Kudova, Eva ; Poso, Antti ; van Beuningen, Rinie ; Pavek, Petr ; Kronenberger, Thales

• Document type: Journal article
• Source: CHEMMEDCHEM; v. N/A, p. 16-pg., 2022-11-30.

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 alpha AF-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 alpha 5/alpha 6 region, alpha AF-2, and alpha 9-11. Changes in the heterodimerization interface induced by antagonists seem to be associated with alpha AF-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. (AU)

• FAPESP's process: 21/11205-9 - Development of new drugs based on the structure of essential proteins for cholesterol synthesis and metabolism, integrating genetic studies and molecular modeling of dyslipidemic patients
• Grantee: Glaucio Monteiro Ferreira
• Support Opportunities: Scholarships in Brazil - Post-Doctoral