Structural basis for specific ligation of the peroxisome proliferator-activated receptor δ.
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.
Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037.|Jack H. Skirball Center for Chemical Biology and Proteomics, The Salk Institute for Biological Studies, La Jolla, CA 92037.
Chyuan-Chuan
CC
Wu
Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037.|Jack H. Skirball Center for Chemical Biology and Proteomics, The Salk Institute for Biological Studies, La Jolla, CA 92037.
Thomas J
TJ
Baiga
Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037.
Michael
M
Downes
Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037.|Jack H. Skirball Center for Chemical Biology and Proteomics, The Salk Institute for Biological Studies, La Jolla, CA 92037.
James J
JJ
La Clair
Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037.
Annette R
AR
Atkins
Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037.|Jack H. Skirball Center for Chemical Biology and Proteomics, The Salk Institute for Biological Studies, La Jolla, CA 92037.
Stephane B
SB
Richard
Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037.
Weiwei
W
Fan
Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037.|Jack H. Skirball Center for Chemical Biology and Proteomics, The Salk Institute for Biological Studies, La Jolla, CA 92037.
Theresa A
TA
Stockley-Noel
Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037.|Jack H. Skirball Center for Chemical Biology and Proteomics, The Salk Institute for Biological Studies, La Jolla, CA 92037.
Marianne E
ME
Bowman
Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037; evans@salk.edu noel@salk.edu.|Jack H. Skirball Center for Chemical Biology and Proteomics, The Salk Institute for Biological Studies, La Jolla, CA 92037.
Joseph P
JP
Noel
Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037; evans@salk.edu noel@salk.edu.|Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037.
Ronald M
RM
Evans
D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D047494:PPAR delta / Q000737:chemistry*; D017434:Protein Structure, Tertiary
D008024:Ligands; D047494:PPAR delta
cation–π interaction; drug discovery; nuclear receptors; peroxisome proliferator-activated receptor; structure-based design