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Human PPARgamma ligand-binding domain R288A mutant in complex with imatinibHuman PPARgamma ligand-binding domain R288A mutant in complex with imatinib
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 PubMedImatinib is an effective anticancer drug for the treatment of leukemia. Interestingly, when an FDA-approved drug library was tested for agents that block peroxisome proliferator-activated receptor gamma (PPARgamma) phosphorylation at Ser245 to evaluate possibilities of antidiabetic drug repositioning, imatinib was determined as a PPARgamma antagonist ligand. However, it is not well understood how imatinib binds to PPARgamma or would improve insulin sensitivity without classical agonism. Here, we report the crystal structure of the PPARgamma R288A mutant in complex with imatinib. Imatinib bound to Arm2 and Arm3 regions in the ligand-binding domain (LBD) of PPARgamma, of which the Arm3 region is closely related to the inhibition of PPARgamma phosphorylation at Ser245. The binding of imatinib in LBD induced a stable conformation of helix H2' and the Omega loop compared with the ligand-free state. In contrast, imatinib does not interact with Tyr473 on PPARgamma helix H12, which is important for the classical agonism associated with side effects. Our study provides new structural insights into the PPARgamma regulation by imatinib and may contribute to the development of new antidiabetic drugs targeting PPARgamma while minimizing known side effects. Structural Basis for the Regulation of PPARgamma Activity by Imatinib.,Jang JY, Kim HJ, Han BW Molecules. 2019 Oct 1;24(19). pii: molecules24193562. doi:, 10.3390/molecules24193562. PMID:31581474[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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