SwePub - sökning: WFRF:(Rashidian Azam)

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1.	Diaz-Holguin, Alejandro, et al. (författare) When Two Become One : Conformational Changes in FXR/RXR Heterodimers Bound to Steroidal Antagonists 2023 Ingår i: ChemMedChem. - : John Wiley & Sons. - 1860-7179 .- 1860-7187. ; 18:4 Tidskriftsartikel (refereegranskat)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.

Diaz-Holguin, Alejandro, et al. (författare)
When Two Become One : Conformational Changes in FXR/RXR Heterodimers Bound to Steroidal Antagonists
2023
Ingår i: ChemMedChem. - : John Wiley & Sons. - 1860-7179 .- 1860-7187. ; 18:4
Tidskriftsartikel (refereegranskat)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.

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