6fzy
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==PPAR mutant== | |
| + | <StructureSection load='6fzy' size='340' side='right' caption='[[6fzy]], [[Resolution|resolution]] 3.10Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6fzy]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FZY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FZY FirstGlance]. <br> | ||
| + | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6fzy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fzy OCA], [http://pdbe.org/6fzy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6fzy RCSB], [http://www.ebi.ac.uk/pdbsum/6fzy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6fzy ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [[http://www.uniprot.org/uniprot/PPARG_HUMAN 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:[http://omim.org/entry/601665 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.<ref>PMID:9753710</ref> Defects in PPARG are the cause of familial partial lipodystrophy type 3 (FPLD3) [MIM:[http://omim.org/entry/604367 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.<ref>PMID:12453919</ref> <ref>PMID:11788685</ref> Genetic variations in PPARG can be associated with susceptibility to glioma type 1 (GLM1) [MIM:[http://omim.org/entry/137800 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 == | ||
| + | [[http://www.uniprot.org/uniprot/PPARG_HUMAN 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.<ref>PMID:9065481</ref> <ref>PMID:16150867</ref> <ref>PMID:20829347</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The 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<ref>PMID:30651555</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 6fzy" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Rochel, N]] | ||
| + | [[Category: Nuclear receptor]] | ||
| + | [[Category: Transcription]] | ||
Revision as of 09:29, 13 February 2019
PPAR mutant
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