title: Revealing a steroid receptor ligand as a unique PPARγ agonist.
abstract: Peroxisome proliferator-activated receptor gamma (PPARγ) 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 PPARγ agonist, thereby uncovering a novel signaling route for this steroid drug. Similar to rosiglitazone, RU-486 modulates the expression of key PPARγ 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 PPARγ 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 PPARγ ligands in the treatment of insulin resistance.
authors: State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China.
authors: Shengchen
authors: S
authors: Lin
authors: Ying
authors: Y
authors: Han
authors: Yuzhe
authors: Y
authors: Shi
authors: Hui
authors: H
authors: Rong
authors: Songyang
authors: S
authors: Zheng
authors: Shikan
authors: S
authors: Jin
authors: Shu-Yong
authors: SY
authors: Lin
authors: Sheng-Cai
authors: SC
authors: Lin
authors: Yong
authors: Y
authors: Li
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008024:Ligands; D015735:Mifepristone / Q000737:chemistry* / Q000494:pharmacology*; D056918:Nuclear Receptor Coactivators / Q000819:agonists / Q000737:chemistry* / Q000235:genetics*; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000737:chemistry
chemical_list: D008024:Ligands; C486559:NCOA6 protein, human; D056918:Nuclear Receptor Coactivators; D045162:Thiazolidinediones; D015735:Mifepristone