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Proc Natl Acad Sci U S A. 2017 Mar 28;114(13):E2563-E2570. doi: 10.1073/pnas.1621513114. Epub 2017 Mar 20.

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

Author information

1
Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037.
2
Jack H. Skirball Center for Chemical Biology and Proteomics, The Salk Institute for Biological Studies, La Jolla, CA 92037.
3
Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037.
4
Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037; evans@salk.edu noel@salk.edu.

Abstract

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.

KEYWORDS:

cation–π interaction; drug discovery; nuclear receptors; peroxisome proliferator-activated receptor; structure-based design

PMID:
28320959
PMCID:
PMC5380080
DOI:
10.1073/pnas.1621513114
[Indexed for MEDLINE]
Free PMC Article

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