3x1h
From Proteopedia
hPPARgamma Ligand binding domain in complex with 5-oxo-tricosahexaenoic acid
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 PubMedCovalent modification of proteins is important for normal cellular regulation. Here, we report on the covalent modification of peroxisome proliferator-activated receptor gamma (PPARgamma), an important drug target, by oxo-fatty acids. In this study, ESI mass spectroscopy showed that the reactivities of oxo-fatty acids with PPARgamma are different from one another and that these behaviors are related to the structure of the fatty acids. X-ray crystallography showed that three oxo-fatty acids all bound to the same residue of PPARgamma (Cys285), but displayed different hydrogen bonding modes. Moreover, fatty acids formed covalent bonds with both PPARgamma moieties in the homodimer, one in an active conformation and the other in an alternative conformation. These two conformations may explain why covalently bound fatty acids show partial rather than full agonist activity. Characterization of Covalent Bond Formation between PPARgamma and Oxo-Fatty Acids.,Egawa D, Itoh T, Yamamoto K Bioconjug Chem. 2015 Mar 26. PMID:25785518[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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