An alternate binding site for PPARγ ligands

PPAR gamma is a target for insulin-sensitizing drugs such as glitazones, which improve plasma glucose maintenance in patients with diabetes. Synthetic ligands have been designed to mimic endogenous ligand binding to a canonical ligand-binding pocket to hyperactivate PPAR gamma. Here we reveal that synthetic PPAR gamma ligands also bind to an alternate site, leading to unique receptor conformational changes that impact coregulator binding, transactivation and target gene expression. Using structure-function studies we show that alternate site binding occurs at pharmacologically relevant ligand concentrations, and is neither blocked by covalently bound synthetic antagonists nor by endogenous ligands indicating non-overlapping binding with the canonical pocket. Alternate site binding likely contributes to PPAR gamma hyperactivation in vivo, perhaps explaining why PPAR gamma full and partial or weak agonists display similar adverse effects. These findings expand our understanding of PPAR gamma activation by ligands and suggest that allosteric modulators could be designed to fine tune PPAR gamma activity without competing with endogenous ligands.