Structure of the PPARα and -γ ligand binding domain in complex with AZ 242;: Ligand selectivity and agonist activation in the PPAR family

Background: The peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors belonging to the nuclear receptor family. The roles of PPAR alpha in fatty acid oxidation and PPAR gamma in adipocyte differentiation and lipid storage have been characterized extensively. PPARs are activated by fatty acids and eicosanoids and are also targets for antidyslipidemic drugs, but the molecular interactions governing ligand selectivity for specific subtypes are unclear due to the lack of a PPAR alpha ligand binding domain structure. Results: We have solved the crystal structure of the PPAR alpha ligand binding domain (LBD) in complex with the combined PPAR alpha and -gamma agonist AZ 242, a novel dihydro cinnamate derivative that is structurally different from thiazolidinediones. In addition, we present the crystal structure of the PPAR gamma -LBD/AZ 242 complex and provide a rationale for ligand selectivity toward the PPAR alpha and -gamma subtypes. Heteronuclear NMR data on PPARa in both the apo form and in complex with AZ 242 shows an overall stabilization of the LBD upon agonist binding. A comparison of the novel PPAR alpha /AZ 242 complex with the PPAR gamma /AZ 242 complex and previously solved PPAR gamma structures reveals a conserved hydrogen bonding network between agonists and the AF2 helix. Conclusions: The complex of PPAR alpha and PPAR gamma with the dual specificity agonist AZ 242 highlights the conserved interactions required for receptor activation. Together with the NMR data, this suggests a general model for ligand activation in the PPAR family. A comparison of the ligand binding sites reveals a molecular explanation for subtype selectivity and provides a basis for rational drug design.