| Autor: |
Chyuan-Chuan Wu, Baiga, Thomas J., Downes, Michael, Clair, James J. La, Atkins, Annette R., Richard, Stephane B., Weiwei Fan, Stockley-Noel, Theresa A., Bowman, Marianne E., Noel, Joseph P., Evans, Ronald M. |
| Předmět: |
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| Zdroj: |
Proceedings of the National Academy of Sciences of the United States of America; 3/28/2017, Vol. 114 Issue 13, pE2563-E2570, 8p, 4 Color Photographs, 1 Diagram |
| Abstrakt: |
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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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