Structural basis for specific ligation of the peroxisome proliferator-activated receptor δ

The peroxisome proliferator-activated receptor (PPAR) family comprises three subtypes: PPAR alpha, PPAR gamma, and PPAR delta. PPAR delta transcriptionally modulates lipid metabolism and the control of energy homeostasis; therefore, PPAR delta agonists are promising agents for treating a variety of metabolic disorders. In the present study, we develop a panel of rationally designed PPAR delta agonists. The modularmotif affords efficient syntheses using building blocks optimized for interactions with subtype-specific residues in the PPARd ligand-binding domain (LBD). A combination of atomic-resolution protein X-ray crystallographic structures, ligand-dependent LBD stabilization assays, and cell-based transactivation measurements delineate structure-activity relationships (SARs) for PPAR delta-selective targeting and structural modulation. We identify key ligand-induced conformational transitions of a conserved tryptophan side chain in the LBD that trigger reorganization of the H2'-H3 surface segment of PPARd. The subtype-specific conservation of H2'-H3 sequences suggests that this architectural remodeling constitutes a previously unrecognized conformational switch accompanying ligand-dependent PPAR delta transcriptional regulation.