5z5s
From Proteopedia
Crystal structure of the PPARgamma-LBD complexed with compound 13ab
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] [PRGC1_HUMAN] Transcriptional coactivator for steroid receptors and nuclear receptors. Greatly increases the transcriptional activity of PPARG and thyroid hormone receptor on the uncoupling protein promoter. Can regulate key mitochondrial genes that contribute to the program of adaptive thermogenesis. Plays an essential role in metabolic reprogramming in response to dietary availability through coordination of the expression of a wide array of genes involved in glucose and fatty acid metabolism.[7] [8] [9] Publication Abstract from PubMedThe lead identification of a novel potent selective PPARgamma agonist, DS-6930 is reported. To avoid PPARgamma-related adverse effects, a partial agonist was designed to prevent the direct interaction with helix 12 of PPARgamma-LBD. Because the TZD group is known to interact with helix 12, the TZD in efatutazone (CS-7017) was replaced to discover novel PPARgamma intermediate partial agonist 8i. The optimization of 8i yielded 13ac with high potency in vitro. Compound 13ac exhibited robust plasma glucose lowering effects comparable to those of rosiglitazone (3mg/kg) in Zucker diabetic fatty rats. Upon toxicological evaluation, compound 13ac (300mg/kg) induced hemodilution to a lower extent than rosiglitazone; however, 13ac elevated liver enzyme activities. X-ray crystallography revealed no direct interaction of 13ac with helix 12, and the additional lipophilic interactions are also suggested to be related to the maximum transcriptional activity of 13ac. Discovery of DS-6930, a potent selective PPARgamma modulator. Part I: Lead identification.,Shinozuka T, Tsukada T, Fujii K, Tokumaru E, Shimada K, Onishi Y, Matsui Y, Wakimoto S, Kuroha M, Ogata T, Araki K, Ohsumi J, Sawamura R, Watanabe N, Yamamoto H, Fujimoto K, Tani Y, Mori M, Tanaka J Bioorg Med Chem. 2018 Oct 1;26(18):5079-5098. doi: 10.1016/j.bmc.2018.09.006., Epub 2018 Sep 8. PMID:30241907[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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