Abstract

Molecular dynamics simulations were performed on two ureidofibrate-like enantiomers to gain insight into their different potency and efficacy against PPARgamma. The partial agonism of the S enantiomer seems to be due to its capability to stabilize different regions of the receptor allowing the interaction with both coactivators and corepressors as shown by fluorescence resonance energy transfer (FRET) assays. The recruitment of the corepressor N-CoR1 by the S enantiomer on two different responsive elements of PPARgamma regulated promoters was confirmed by chromatin immunoprecipitation assays. Cell-based transcription assays show that PPARgamma coactivator 1alpha (PGC-1alpha) and cAMP response element binding protein-binding protein (CBP) enhance the basal and ligand-stimulated receptor activity acting as coactivators of PPARgamma, whereas the receptor interacting protein 140 (RIP140) and the nuclear corepressor 1 (N-CoR1) repress the transcriptional activity of PPARgamma. We also tested the importance of the residue Q286 on the transcriptional activity of the receptor by site-directed mutagenesis and confirmed its key role in the stabilization of helix 12. Molecular modeling studies were performed to provide a molecular explanation for the different behavior of the mutants.

Autore Pugliese

• Laghezza Antonio , Loiodice Fulvio , Fracchiolla Giuseppe , Tortorella Paolo

Tutti gli autori

• LAGHEZZA A.;LOIODICE F.;FRACCHIOLLA G.;TORTORELLA P.

Titolo volume/Rivista

Non Disponibile

Anno di pubblicazione

2010

ISSN

0022-2623

ISBN

Non Disponibile

Numero di citazioni Wos

21

Ultimo Aggiornamento Citazioni

Non Disponibile

Numero di citazioni Scopus

23

Ultimo Aggiornamento Citazioni

Non Disponibile

Settori ERC

Non Disponibile

Codici ASJC

Non Disponibile