| Texto completo | |
| Autor(es): Mostrar menos - |
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
Número total de Autores: 11
|
| Tipo de documento: | Artigo Científico |
| Fonte: | CHEMMEDCHEM; v. N/A, p. 16-pg., 2022-11-30. |
| Resumo | |
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) | |
| Processo FAPESP: | 21/11205-9 - Desenvolvimento de novos fármacos baseados na estrutura de proteínas essenciais para síntese e metabolismo do colesterol, integrando estudos genéticos e modelagem molecular de pacientes dislipidêmicos |
| Beneficiário: | Glaucio Monteiro Ferreira |
| Modalidade de apoio: | Bolsas no Brasil - Pós-Doutorado |