4ci5
Structural basis for GL479 a dual Peroxisome Proliferator-Activated Receptor gamma agonist
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 PubMedPeroxisome Proliferator-Activated Receptors (PPARs) are ligand-dependent transcription factors that control various functions in human organism, including the control of glucose and lipid metabolism. PPARgamma is a target of TZD agonists, clinically used to improve insulin sensitivity whereas fibrates, PPARalpha ligands, lower serum triglyceride levels. We report here the structural studies of GL479, a synthetic dual PPARalpha/gamma agonist, designed by a combination of clofibric acid skeleton and a phenyldiazenyl moiety, as bioisosteric replacement of stilbene group, in complex with both PPARalpha and PPARgamma receptors. GL479 was previously reported as a partial agonist of PPARgamma and a full agonist of PPARalpha with high affinity for both PPARs. Our structural studies reveal different binding modes of GL479 to PPARalpha and PPARgamma, which may explain the distinct activation behaviors observed for each receptor. In both cases the ligand interacts with a Tyr located at helix 12 (H12), resulting in the receptor active conformation. In the complex with PPARalpha, GL479 occupies the same region of the ligand-binding pocket (LBP) observed for other full agonists, whereas GL479 bound to PPARgamma displays a new binding mode. Our results indicate a novel region of PPARs LBP that may be explored for the design of partial agonists as well dual PPARalpha/gamma agonists that combine, simultaneously, the therapeutic effects of the treatment of insulin resistance and dyslipidemia. Different binding and recognition modes of GL479, a dual agonist of Peroxisome Proliferator-Activated Receptor alpha/gamma.,Dos Santos JC, Bernardes A, Giampietro L, Ammazzalorso A, De Filippis B, Amoroso R, Polikarpov I J Struct Biol. 2015 Jul 14. pii: S1047-8477(15)30031-9. doi:, 10.1016/j.jsb.2015.07.006. PMID:26185032[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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