4yt1 | pdb_00004yt1
Human PPAR Gamma Ligand Binding Domain in complex with a Gammma Selective Synthetic Partial Agonist MEKT76
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 PubMedIn the course of studies directed toward the creation of human peroxisome proliferator-activated receptor gamma (hPPARgamma) partial agonists, we designed and synthesized benzylsulfonylaminocarbonyl derivative (3) by structural modification of our reported hPPARgamma partial agonist 2. Co-crystallization of 3 with the hPPARgamma ligand-binding domain (LBD) afforded a homodimeric complex in which one of the LBDs adopts a fully active structure without bound 3, while the other LBD exhibits a non-fully active structure containing one molecule of bound 3. Interestingly, 2 and 3 are structurally similar, but bind to hPPARgamma LBD in distinct conformations, that is, the sulfonylaminocarbonyl moiety of bound 3 is directed at 180 degrees away from that of bound 2. These results support our previous proposal that the hPPARgamma LBD has multiple binding points that can be utilized to accommodate structurally flexible hPPAR ligands. Peroxisome proliferator-activated receptor gamma (PPARgamma) has multiple binding points that accommodate ligands in various conformations: Structurally similar PPARgamma partial agonists bind to PPARgamma LBD in different conformations.,Ohashi M, Gamo K, Oyama T, Miyachi H Bioorg Med Chem Lett. 2015 Jul 15;25(14):2758-62. doi:, 10.1016/j.bmcl.2015.05.025. Epub 2015 May 22. PMID:26025876[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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