7awc | pdb_00007awc
Crystal structure of Peroxisome proliferator-activated receptor gamma (PPARG)in complex with rosiglitazone
Structural highlights
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.[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. 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.[4] [5] [6] Publication Abstract from PubMedVitamin E exhibits pharmacological effects beyond established antioxidant activity suggesting involvement of unidentified mechanisms. Here, we characterize endogenously formed tocopherol carboxylates and the vitamin E mimetic garcinoic acid (GA) as activators of the peroxisome proliferator-activated receptor gamma (PPARgamma). Co-stimulation of PPARgamma with GA and the orthosteric agonist pioglitazone resulted in additive transcriptional activity. In line with this, the PPARgamma-GA complex adopted a fully active conformation and interestingly contained two bound GA molecules with one at an allosteric site. A co-regulator interaction scan demonstrated an unanticipated co-factor recruitment profile for GA-bound PPARgamma compared with canonical PPARgamma agonists and gene expression analysis revealed different effects of GA and pioglitazone on PPAR signaling in hepatocytes. These observations reveal allosteric mechanisms of PPARgamma modulation as an alternative avenue to PPARgamma targeting and suggest contributions of PPARgamma activation by alpha-13-tocopherolcarboxylate to the pharmacological effects of vitamin E. Endogenous vitamin E metabolites mediate allosteric PPARgamma activation with unprecedented co-regulatory interactions.,Willems S, Gellrich L, Chaikuad A, Kluge S, Werz O, Heering J, Knapp S, Lorkowski S, Schubert-Zsilavecz M, Merk D Cell Chem Biol. 2021 Oct 21;28(10):1489-1500.e8. doi:, 10.1016/j.chembiol.2021.04.019. Epub 2021 May 13. PMID:33989565[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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