Journal
CELL RESEARCH
Volume 22, Issue 4, Pages 746-756Publisher
INST BIOCHEMISTRY & CELL BIOLOGY
DOI: 10.1038/cr.2011.162
Keywords
PPAR gamma; nuclear receptor; diabetes; crystal structure; steroid compound
Categories
Funding
- Office of Science of the US Department of Energy
- National Institutes of Health [DK081757]
- National Natural Science Foundation of China [31070646, 30730025]
- Science Planning Program of Fujian Province [2009J1010]
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Peroxisome proliferator-activated receptor gamma (PPAR gamma) regulates metabolic homeostasis and is a molecular target for anti-diabetic drugs. We report here the identification of a steroid receptor ligand, RU-486, as an unexpected PPAR gamma agonist, thereby uncovering a novel signaling route for this steroid drug. Similar to rosiglitazone, RU-486 modulates the expression of key PPAR gamma target genes and promotes adipocyte differentiation, but with a lower adipogenic activity. Structural and functional studies of receptor-ligand interactions reveal the molecular basis for a unique binding mode for RU-486 in the PPAR gamma ligand-binding pocket with distinctive properties and epitopes, providing the molecular mechanisms for the discrimination of RU-486 from thiazolidinediones (TZDs) drugs. Our findings together indicate that steroid compounds may represent an alternative approach for designing non-TZD PPAR gamma ligands in the treatment of insulin resistance.
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