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

Chyuan Chuan Wu, Thomas J. Baiga, Michael Downes, James J. la Clair, Annette R. Atkins, Stephane B. Richard, Weiwei Fan, Theresa A. Stockley-Noel, Marianne E. Bowman, Joseph P. Noel, Ronald M. Evans

Research output: Contribution to journalArticlepeer-review

38 Citations (Scopus)


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.

Original languageEnglish
Article numberE2563
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number13
Publication statusPublished - 2017 Mar 28

All Science Journal Classification (ASJC) codes

  • General


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