6fzg | pdb_00006fzg
PPAR gamma mutant complex
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 PubMedThe upregulation of PPARgamma/RXRalpha transcriptional activity has emerged as a key event in luminal bladder tumors. It renders tumor cell growth PPARgamma-dependent and modulates the tumor microenvironment to favor escape from immuno-surveillance. The activation of the pathway has been linked to PPARG gains/amplifications resulting in PPARgamma overexpression and to recurrent activating point mutations of RXRalpha. Here, we report recurrent mutations of PPARgamma that also activate the PPARgamma/RXRalpha pathway, conferring PPARgamma-dependency and supporting a crucial role of PPARgamma in luminal bladder cancer. These mutations are found throughout the protein-including N-terminal, DNA-binding and ligand-binding domains-and most of them enhance protein activity. Structure-function studies of PPARgamma variants with mutations in the ligand-binding domain allow identifying structural elements that underpin their gain-of-function. Our study reveals genomic alterations of PPARG that lead to pro-tumorigenic PPARgamma/RXRalpha pathway activation in luminal bladder tumors and may open the way towards alternative options for treatment. Recurrent activating mutations of PPARgamma associated with luminal bladder tumors.,Rochel N, Krucker C, Coutos-Thevenot L, Osz J, Zhang R, Guyon E, Zita W, Vanthong S, Hernandez OA, Bourguet M, Badawy KA, Dufour F, Peluso-Iltis C, Heckler-Beji S, Dejaegere A, Kamoun A, de Reynies A, Neuzillet Y, Rebouissou S, Beraud C, Lang H, Massfelder T, Allory Y, Cianferani S, Stote RH, Radvanyi F, Bernard-Pierrot I Nat Commun. 2019 Jan 16;10(1):253. doi: 10.1038/s41467-018-08157-y. PMID:30651555[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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