6y3u
Crystal structure of PPARgamma in complex with compound (R)-16
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 PubMedThe nuclear peroxisome proliferator-activated receptor gamma has well-validated therapeutic potential in metabolic, inflammatory, and neurodegenerative pathologies, but its activation is also associated with marked adverse effects and novel modes of PPARgamma modulation are required. Here, we report the discovery and profiling of a new PPARgamma modulator chemotype endowed with remarkable potency and a distinct binding mode in the orthosteric PPARgamma ligand-binding site. Its R-enantiomer evolved as a eutomer regarding PPARgamma activation with a high eudysmic ratio. The new PPARgamma modulator revealed outstanding selectivity over the PPARalpha and PPARdelta subtypes and did not promote adipogenesis in primary human fibroblasts, discriminating it from established agonists. A Selective Modulator of Peroxisome Proliferator-Activated Receptor gamma with an Unprecedented Binding Mode.,Hanke T, Cheung SY, Kilu W, Heering J, Ni X, Planz V, Schierle S, Faudone G, Friedrich M, Wanior M, Werz O, Windbergs M, Proschak E, Schubert-Zsilavecz M, Chaikuad A, Knapp S, Merk D J Med Chem. 2020 Apr 20. doi: 10.1021/acs.jmedchem.9b01786. PMID:32267688[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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