View source for 4xta


==MECHANISMS OF PPARgamma ACTIVATION BY NON-STEROIDAL ANTI-INFLAMMATORY DRUGS==
<StructureSection load='4xta' size='340' side='right'caption='[[4xta]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4xta]] 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=4XTA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XTA FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DIF:2-[2,6-DICHLOROPHENYL)AMINO]BENZENEACETIC+ACID'>DIF</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=4xta FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xta OCA], [https://pdbe.org/4xta PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xta RCSB], [https://www.ebi.ac.uk/pdbsum/4xta PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xta 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> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Non-steroidal anti-inflammatory drugs (NSAIDs) display anti-inflammatory, antipyretic and analgesic properties by inhibiting cyclooxygenases and blocking prostaglandin production. Previous studies, however, suggested that some NSAIDs also modulate peroxisome proliferator activated receptors (PPARs), raising the possibility that such off target effects contribute to the spectrum of clinically relevant NSAID actions. In this study, we set out to understand how peroxisome proliferator activated receptor-gamma (PPARgamma/PPARG) interacts with NSAIDs using X-ray crystallography and to relate ligand binding modes to effects on receptor activity. We find that several NSAIDs (sulindac sulfide, diclofenac, indomethacin and ibuprofen) bind PPARgamma and modulate PPARgamma activity at pharmacologically relevant concentrations. Diclofenac acts as a partial agonist and binds to the PPARgamma ligand binding pocket (LBP) in typical partial agonist mode, near the beta-sheets and helix 3. By contrast, two copies of indomethacin and sulindac sulfide bind the LBP and, in aggregate, these ligands engage in LBP contacts that resemble agonists. Accordingly, both compounds, and ibuprofen, act as strong partial agonists. Assessment of NSAID activities in PPARgamma-dependent 3T3-L1 cells reveals that NSAIDs display adipogenic activities and exclusively regulate PPARgamma-dependent target genes in a manner that is consistent with their observed binding modes. Further, PPARgamma knockdown eliminates indomethacin activities at selected endogenous genes, confirming receptor-dependence of observed effects. We propose that it is important to consider how individual NSAIDs interact with PPARgamma to understand their activities, and that it will be interesting to determine whether high dose NSAID therapies result in PPAR activation.

Mechanisms of peroxisome proliferator activated receptor gamma regulation by non-steroidal anti-inflammatory drugs.,Puhl AC, Milton FA, Cvoro A, Sieglaff DH, Campos JC, Bernardes A, Filgueira CS, Lindemann JL, Deng T, Neves FA, Polikarpov I, Webb P Nucl Recept Signal. 2015 Oct 5;13:e004. doi: 10.1621/nrs.13004. eCollection 2015. PMID:26445566<ref>PMID:26445566</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4xta" 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: Polikarpov I]]
[[Category: Puhl AC]]
[[Category: Webb P]]