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

TLDR

The peroxisome proliferator‑activated receptors (PPARs) are transcriptional regulators of glucose, lipid, and cholesterol metabolism. The availability of high‑resolution cocrystal structures of the three PPAR subtypes will aid the design of drugs for the treatment of metabolic and cardiovascular diseases. We report the x‑ray crystal structure of the ligand binding domain of PPARα (NR1C1) as a complex with the agonist ligand GW409544 and a coactivator motif from the steroid receptor coactivator 1. Comparison of the crystal structures of the ligand binding domains of the three human PPARs identified molecular determinants of subtype selectivity, including a single amino acid (tyrosine in PPARα versus histidine in PPARγ) that imparts selectivity for both thiazolidinedione and nonthiazolidinedione ligands.

Abstract

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 PPARα (NR1C1) as a complex with the agonist ligand GW409544 and a coactivator motif from the steroid receptor coactivator 1. Through comparison of the crystal structures of the ligand binding domains of the three human PPARs, we have identified molecular determinants of subtype selectivity. A single amino acid, which is tyrosine in PPARα and histidine in PPARγ, imparts subtype selectivity for both thiazolidinedione and nonthiazolidinedione ligands. The availability of high-resolution cocrystal structures of the three PPAR subtypes will aid the design of drugs for the treatments of metabolic and cardiovascular diseases.