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Crystal structure of the complex between PPARgamma LBD and trans-resveratrolCrystal structure of the complex between PPARgamma LBD and trans-resveratrol
Structural highlights
DiseasePPARG_HUMAN Note=Defects in PPARG can lead to type 2 insulin-resistant diabetes and hyptertension. PPARG mutations may be associated with colon cancer. Defects in PPARG may be associated with susceptibility to obesity (OBESITY) [MIM:601665. It is a condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat.[1] Defects in PPARG are the cause of familial partial lipodystrophy type 3 (FPLD3) [MIM:604367. Familial partial lipodystrophies (FPLD) are a heterogeneous group of genetic disorders characterized by marked loss of subcutaneous (sc) fat from the extremities. Affected individuals show an increased preponderance of insulin resistance, diabetes mellitus and dyslipidemia.[2] [3] Genetic variations in PPARG can be associated with susceptibility to glioma type 1 (GLM1) [MIM:137800. Gliomas are central nervous system neoplasms derived from glial cells and comprise astrocytomas, glioblastoma multiforme, oligodendrogliomas, and ependymomas. Note=Polymorphic PPARG alleles have been found to be significantly over-represented among a cohort of American patients with sporadic glioblastoma multiforme suggesting a possible contribution to disease susceptibility. FunctionPPARG_HUMAN Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the receptor binds to a promoter element in the gene for acyl-CoA oxidase and activates its transcription. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses.[4] [5] [6] Publication Abstract from PubMedResveratrol, a modulator of several signaling proteins, can exert off-target effects involving the peroxisome proliferator-activated receptor (PPAR) transcription factors. However, evidence for the direct interaction between this polyphenol and PPARs is lacking. Here, we addressed the hypothesis that resveratrol and its metabolites control aspects of PPAR transcriptional activity through direct interaction with PPARs. Bioaffinity chromatographic studies with the immobilized ligand-binding domains (LBDs) of PPARgamma and PPARalpha and isothermal titration calorimetry allowed the binding affinities of resveratrol, resveratrol 3-O-glucuronide, resveratrol 4-O-glucuronide, and resveratrol 3-O-sulfate to both PPAR-LBDs to be determined. Interaction of resveratrol, resveratrol 3-O-glucuronide, and resveratrol 4-O-glucuronide with PPARgamma-LBD occurred with binding affinities of 1.4, 1.1, and 0.8 muM, respectively, although only resveratrol bound to the PPARalpha-LBD with a binding affinity of 2.7 muM. Subsequently, X-ray crystallographic studies were carried out to characterize resveratrol binding to the PPARgamma-LBD at the molecular level. The electron density map from the crystal structure of the complex between PPARgamma-LBD and resveratrol revealed the presence of one molecule of resveratrol bound to the LBD of PPARgamma, with the ligand occupying a position close to that of other known PPARgamma ligands. Transactivation assays were also performed in HepG2 cells, with the results showing that resveratrol was not a PPAR agonist but instead was able to displace rosiglitazone from PPARgamma and Wy-14643 from PPARalpha with IC50 values of (27.4+/-1.8) muM and (31.7+/-2.5) muM, respectively. We propose that resveratrol acts as a PPAR antagonist through its direct interaction with PPARgamma and PPARalpha. Resveratrol and Its Metabolites Bind to PPARs.,Calleri E, Pochetti G, Dossou KS, Laghezza A, Montanari R, Capelli D, Prada E, Loiodice F, Massolini G, Bernier M, Moaddel R Chembiochem. 2014 May 26;15(8):1154-60. doi: 10.1002/cbic.201300754. Epub 2014, May 5. PMID:24796862[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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