View source for 7wgp


==X-ray structure of human PPAR gamma ligand binding domain-fenofibric acid co-crystals obtained by co-crystallization==
<StructureSection load='7wgp' size='340' side='right'caption='[[7wgp]], [[Resolution|resolution]] 2.53&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7wgp]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7WGP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7WGP FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.53&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=F5A:2-[4-(4-chlorobenzene-1-carbonyl)phenoxy]-2-methylpropanoic+acid'>F5A</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7wgp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7wgp OCA], [https://pdbe.org/7wgp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7wgp RCSB], [https://www.ebi.ac.uk/pdbsum/7wgp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7wgp ProSAT]</span></td></tr>
</table>
== Disease ==
[https://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:[https://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:[https://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:[https://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 ==
[https://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> 
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== Publication Abstract from PubMed ==
Among the agonists against three peroxisome proliferator-activated receptor (PPAR) subtypes, those against PPARalpha (fibrates) and PPARgamma (glitazones) are currently used to treat dyslipidemia and type 2 diabetes, respectively, whereas PPARdelta agonists are expected to be the next-generation metabolic disease drug. In addition, some dual/pan PPAR agonists are currently being investigated via clinical trials as one of the first curative drugs against nonalcoholic fatty liver disease (NAFLD). Because PPARalpha/delta/gamma share considerable amino acid identity and three-dimensional structures, especially in ligand-binding domains (LBDs), clinically approved fibrates, such as bezafibrate, fenofibric acid, and pemafibrate, could also act on PPARdelta/gamma when used as anti-NAFLD drugs. Therefore, this study examined their PPARalpha/delta/gamma selectivity using three independent assays-a dual luciferase-based GAL4 transactivation assay for COS-7 cells, time-resolved fluorescence resonance energy transfer-based coactivator recruitment assay, and circular dichroism spectroscopy-based thermostability assay. Although the efficacy and efficiency highly varied between agonists, assay types, and PPAR subtypes, the three fibrates, except fenofibric acid that did not affect PPARdelta-mediated transactivation and coactivator recruitment, activated all PPAR subtypes in those assays. Furthermore, we aimed to obtain cocrystal structures of PPARdelta/gamma-LBD and the three fibrates via X-ray diffraction and versatile crystallization methods, which we recently used to obtain 34 structures of PPARalpha-LBD cocrystallized with 17 ligands, including the fibrates. We herein reveal five novel high-resolution structures of PPARdelta/gamma-bezafibrate, PPARgamma-fenofibric acid, and PPARdelta/gamma-pemafibrate, thereby providing the molecular basis for their application beyond dyslipidemia treatment.

Functional and Structural Insights into Human PPARalpha/delta/gamma Subtype Selectivity of Bezafibrate, Fenofibric Acid, and Pemafibrate.,Honda A, Kamata S, Akahane M, Machida Y, Uchii K, Shiiyama Y, Habu Y, Miyawaki S, Kaneko C, Oyama T, Ishii I Int J Mol Sci. 2022 Apr 25;23(9). pii: ijms23094726. doi: 10.3390/ijms23094726. PMID:35563117<ref>PMID:35563117</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 7wgp" style="background-color:#fffaf0;"></div>

==See Also==
*[[Peroxisome proliferator-activated receptor 3D structures|Peroxisome proliferator-activated receptor 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Akahane M]]
[[Category: Honda A]]
[[Category: Ishii I]]
[[Category: Kamata S]]
[[Category: Machida Y]]
[[Category: Masuda R]]
[[Category: Oyama T]]
[[Category: Shiiyama Y]]
[[Category: Uchii K]]