TY - JOUR
T1 - Structural basis for specific ligation of the peroxisome proliferator-activated receptor δ
AU - Wu, Chyuan Chuan
AU - Baiga, Thomas J.
AU - Downes, Michael
AU - la Clair, James J.
AU - Atkins, Annette R.
AU - Richard, Stephane B.
AU - Fan, Weiwei
AU - Stockley-Noel, Theresa A.
AU - Bowman, Marianne E.
AU - Noel, Joseph P.
AU - Evans, Ronald M.
N1 - Publisher Copyright:
© 2017 National Academy of Sciences. All rights reserved.
PY - 2017/3/28
Y1 - 2017/3/28
N2 - 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.
AB - 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.
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U2 - 10.1073/PNAS.1621513114
DO - 10.1073/PNAS.1621513114
M3 - Article
C2 - 28320959
AN - SCOPUS:85032052360
VL - 114
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 13
M1 - E2563
ER -