Insights into the Mechanism of Partial Agonism: Crystal Structures of the Peroxisome Proliferator-activated Receptor-gamma Ligand-Binding Domain in the Complex with Two Enantiomeric Ligands
Abstract
The peroxisome proliferator-activated receptors (PPARs) are transcriptional regulators of glucose and lipid metabolism. They are activated by natural ligands, such as fatty acids, and are also target of synthetic antidiabetic and hypolipidemic drugs. By using cell-based reporter assays, we studied the transactivation activity of two enantiomeric ureidofibrate derivatives. In particular, we show that the R-enantiomer, is a full agonist of PPAR-gamma, whereas the S-enantiomer, is a less potent partial agonist.
These two molecules affect specifically the transcriptional activity of PPAR-alpha and gamma subtypes, whereas the activity of other members of the nuclear receptor gene superfamily is not altered. Most importantly, we report the X-ray crystal structures of the PPAR-gamma ligand binding domain respectively complexed with the R- and the S-enantiomer. The analysis of the two crystal structures shows that the different degree of stabilization of the helix 12 induced by the ligand determines its behaviour as full or partial agonist.
The peroxisome proliferator-activated receptors (PPARs) are transcriptional regulators of glucose and lipid metabolism. They are activated by natural ligands, such as fatty acids, and are also target of synthetic antidiabetic and hypolipidemic drugs. By using cell-based reporter assays, we studied the transactivation activity of two enantiomeric ureidofibrate derivatives. In particular, we show that the R-enantiomer, is a full agonist of PPAR-gamma, whereas the S-enantiomer, is a less potent partial agonist.
These two molecules affect specifically the transcriptional activity of PPAR-alpha and gamma subtypes, whereas the activity of other members of the nuclear receptor gene superfamily is not altered. Most importantly, we report the X-ray crystal structures of the PPAR-gamma ligand binding domain respectively complexed with the R- and the S-enantiomer. The analysis of the two crystal structures shows that the different degree of stabilization of the helix 12 induced by the ligand determines its behaviour as full or partial agonist.
