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

ABSTRACT: The peroxisome proliferator-activated receptor (PPAR) family comprises three subtypes: PPAR?, PPAR?, and PPAR?. PPAR? transcriptionally modulates lipid metabolism and the control of energy homeostasis; therefore, PPAR? agonists are promising agents for treating a variety of metabolic disorders. In the present study, we develop a panel of rationally designed PPAR? agonists. The modular motif affords efficient syntheses using building blocks optimized for interactions with subtype-specific residues in the PPAR? 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?-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 PPAR?. The subtype-specific conservation of H2'-H3 sequences suggests that this architectural remodeling constitutes a previously unrecognized conformational switch accompanying ligand-dependent PPAR? transcriptional regulation.

SUBMITTER: Wu CC 

PROVIDER: S-EPMC5380080 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature