5u5l
X-ray Crystal Structure of the PPARgamma Ligand Binding Domain in Complex with Rivoglitazone
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 PubMedThiazolidinedione (TZD) compounds targeting the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) demonstrate unique benefits for the treatment of insulin resistance and type II diabetes. TZDs include rosiglitazone, pioglitazone and rivoglitazone, with the latter being the most potent. The TZDs are only marginally selective for the therapeutic target PPARgamma as they also activate PPARalpha and PPARdelta homologues to varying degrees, causing off-target effects. While crystal structures for TZD compounds in complex with PPARgamma are available, minimal structural information is available for TZDs bound to PPARalpha and PPARdelta. This paucity of structural information has hampered the determination of precise structural mechanisms involved in TZD selectivity between PPARs. To help address these questions molecular dynamic simulations were performed of rosiglitazone, pioglitazone and rivoglitazone in complex with PPARalpha, PPARdelta, and PPARgamma in order to better understand the mechanisms of PPAR selectivity. The simulations revealed that TZD interactions with residues Tyr314 and Phe318 of PPARalpha and residues Phe291 and Thr253 of PPARdelta as well as the omega loop, are key determinants of TZD receptor selectivity. Notably, in this study, we solve the first X-ray crystal structure of rivoglitazone bound to any PPAR. Rivoglitazone forms a unique hydrogen bond network with the residues of the PPARgamma co-activator binding surface (known as AF2) and makes more extensive contacts with helix 3 and the beta-sheet as compared to model TZD compounds such as rosiglitazone. X-ray crystal structure of rivoglitazone bound to PPARgamma and PPAR subtype selectivity of TZDs.,Rajapaksha H, Bhatia H, Wegener K, Petrovsky N, Bruning JB Biochim Biophys Acta. 2017 Aug;1861(8):1981-1991. doi:, 10.1016/j.bbagen.2017.05.008. Epub 2017 May 9. PMID:28499821[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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