Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors

The peroxisome proliferator-activated receptors (PPARs) are transcriptional regulators of glucose, lipid, and cholesterol metabolism. We report the x- ray crystal structure of the ligand binding domain of PPAR alpha (NR1C1) as a complex with the agonist ligand GW409544 and a coactivator motif from th e steroid receptor coactivator 1. Through comparison of the crystal structu res of the ligand binding domains of the three human PPARs, we have identif ied molecular determinants of subtype selectivity. A single amino acid, whi ch is tyrosine in PPAR alpha and histidine in PPAR gamma, imparts subtype s electivity for both thiazolidinedione and nonthiazolidinedione ligands. The availability of high-resolution cocrystal structures of the three PPAR sub types will aid the design of drugs for the treatments of metabolic and card iovascular diseases.