7e0a

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 7e0a is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.771Å Ligands: Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease PPARG_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. 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. 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. Function PPARG_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. Publication Abstract from PubMed Peroxisome 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Peroxisome proliferator-activated receptor 3D structures

spinqualitylabelsall models 7e0a, resolution 1.77Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image