Subtype specific effects of peroxisome proliferator-activated receptor ligands on corepressor affinity.

Natural ligands for nuclear receptors are believed to activate gene transcription by causing dissociation of corepressors and promoting the association of coactivator proteins. Using multiple biophysical techniques, we find that peptides derived from one of the nuclear receptor interacting motifs of the corepressors nuclear receptor corepressor (NCoR) and silencing mediator of retinoid and thyroid receptors (SMRT) are able to bind the ligand binding domains (LBD) of all three PPAR (peroxisome proliferator activated receptor) subtypes. Using these peptides as tools, we find that ligands designed as selective agonists for PPAR gamma promote the association of coactivator peptides and dissociation of corepressor peptides as expected on PPAR gamma but surprisingly have varied effects on the binding of corepressor peptides to the other PPAR subtypes. In particular, some members of a class of L-tyrosine-based compounds designed as selective agonists for PPAR gamma reduce the affinity for corepressor peptides on PPAR gamma but increase the affinity for the same peptides on PPAR delta and in one case on PPAR alpha. We provide structural data that suggests that the molecular basis for these observations are variations in the ligand binding pockets of the three PPAR subtypes that are perturbed differentially by individual ligands and result in altered presentations of the overlapping coactivator/corepressor binding surfaces.