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X-ray structure of human PPARgamma ligand binding domain-saroglitazar co-crystals obtained by co-crystallizationX-ray structure of human PPARgamma ligand binding domain-saroglitazar co-crystals obtained by co-crystallization
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 nuclear receptor-type transcription factors that consist of three subtypes (alpha, gamma, and beta/delta) with distinct functions and PPAR dual/pan agonists are expected to be the next generation of drugs for metabolic diseases. Saroglitazar is the first clinically approved PPARalpha/gamma dual agonist for treatment of diabetic dyslipidemia and is currently in clinical trials to treat non-alcoholic fatty liver disease (NAFLD); however, the structural information of its interaction with PPARalpha/gamma remains unknown. We recently revealed the high-resolution co-crystal structure of saroglitazar and the PPARalpha-ligand binding domain (LBD) through X-ray crystallography, and in this study, we report the structure of saroglitazar and the PPARgamma-LBD. Saroglitazar was located at the center of "Y"-shaped PPARgamma-ligand-binding pocket (LBP), just as it was in the respective region of PPARalpha-LBP. Its carboxylic acid was attached to four amino acids (Ser289/His323/His449/Thr473), which contributes to the stabilization of Activating Function-2 helix 12, and its phenylpyrrole moiety was rotated 121.8 degrees in PPARgamma-LBD from that in PPARalpha-LBD to interact with Phe264. PPARdelta-LBD has the consensus four amino acids (Thr253/His287/His413/Tyr437) towards the carboxylic acids of its ligands, but it seems to lack sufficient space to accept saroglitazar because of the steric hindrance between the Trp228 or Arg248 residue of PPARdelta-LBD and its methylthiophenyl moiety. Accordingly, in a coactivator recruitment assay, saroglitazar activated PPARalpha-LBD and PPARgamma-LBD but not PPARdelta-LBD, whereas glycine substitution of either Trp228, Arg248, or both of PPARdelta-LBD conferred saroglitazar concentration-dependent activation. Our findings may be valuable in the molecular design of PPARalpha/gamma dual or PPARalpha/gamma/delta pan agonists. Structural Basis for Anti-non-alcoholic Fatty Liver Disease and Diabetic Dyslipidemia Drug Saroglitazar as a PPAR alpha/gamma Dual Agonist.,Honda A, Kamata S, Satta C, Machida Y, Uchii K, Terasawa K, Nemoto A, Oyama T, Ishii I Biol Pharm Bull. 2021;44(9):1210-1219. doi: 10.1248/bpb.b21-00232. PMID:34471049[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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