期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2017
卷号：114
期号：13
页码：E2563-E2570
DOI：10.1073/pnas.1621513114
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：The peroxisome proliferator-activated receptor (PPAR) family comprises three subtypes: PPARα, PPARγ, and PPARδ. PPARδ transcriptionally modulates lipid metabolism and the control of energy homeostasis; therefore, PPARδ agonists are promising agents for treating a variety of metabolic disorders. In the present study, we develop a panel of rationally designed PPARδ agonists. The modular motif affords efficient syntheses using building blocks optimized for interactions with subtype-specific residues in the PPARδ 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 PPARδ-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 PPARδ. The subtype-specific conservation of H2′–H3 sequences suggests that this architectural remodeling constitutes a previously unrecognized conformational switch accompanying ligand-dependent PPARδ transcriptional regulation.
