Abstract

In this study we report the behavior of two PPAR enantiomeric ligands (R-1 and S-1). Cell-based reporter assays indicate that both enantiomers are dual PPAR/ ligands, being R-1 a full agonist of PPAR and and S-1 a partial agonist of PPAR. 3D-structure analysis of the PPAR ligand binding domain in the complex with the two ligands shows that the suboptimal conformation of helix 12 in the PPAR/S-1 complex is the consequence of a steric hindrance between the ethyl group of the ligand and the Q286 in helix 3. Site-directed mutagenesis confirms that Q286 is a key residue in determining the activity of different ligands. By using FRET assays, we found that the coactivators SRC-1, PGC-1, RIP140, TIF-2 are recruited by R-1, S-1 and rosiglitazone with similar EC50, whereas CBP affinity is higher in the presence of rosiglitazone. Conversely, only S-1 allows the association of the corepressor N-CoR to PPAR as opposed to rosiglitazone and R-1, providing a functional explanation to the partial agonist behavior of S-1. ChIP assays confirmed that S-1 enhances the association of N-CoR to PPAR target promoters in the native chromatin context, whereas rosiglitazone and R-1 recruit less N-CoR. Altogether, our results provide a rationale for the distinct behavior of different PPAR ligands.

Autore Pugliese

• Fracchiolla Giuseppe , Tortorella Paolo

Tutti gli autori

• FRACCHIOLLA G.;TORTORELLA P.

Titolo volume/Rivista

Non Disponibile

Anno di pubblicazione

2010

ISSN

0892-6638

ISBN

Non Disponibile

Numero di citazioni Wos

Nessuna citazione

Ultimo Aggiornamento Citazioni

Non Disponibile

Numero di citazioni Scopus

Non Disponibile

Ultimo Aggiornamento Citazioni

Non Disponibile

Settori ERC

Non Disponibile

Codici ASJC

Non Disponibile