7e2o: Difference between revisions
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==X-ray Crystal structure of PPARgamma R288H mutant.== | ==X-ray Crystal structure of PPARgamma R288H mutant.== | ||
<StructureSection load='7e2o' size='340' side='right'caption='[[7e2o]]' scene=''> | <StructureSection load='7e2o' size='340' side='right'caption='[[7e2o]], [[Resolution|resolution]] 3.20Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7E2O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7E2O FirstGlance]. <br> | <table><tr><td colspan='2'>[[7e2o]] 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=7E2O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7E2O FirstGlance]. <br> | ||
</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=7e2o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7e2o OCA], [https://pdbe.org/7e2o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7e2o RCSB], [https://www.ebi.ac.uk/pdbsum/7e2o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7e2o ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.2Å</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=7e2o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7e2o OCA], [https://pdbe.org/7e2o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7e2o RCSB], [https://www.ebi.ac.uk/pdbsum/7e2o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7e2o ProSAT]</span></td></tr> | |||
</table> | </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 == | |||
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor and the molecular target of thiazolidinedione-class antidiabetic drugs. It has been reported that the loss of function R288H mutation in the human PPARgamma ligand-binding domain (LBD) may be associated with the onset of colon cancer. A previous in vitro study showed that this mutation dampens 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2, a natural PPARgamma agonist)-dependent transcriptional activation; however, it is poorly understood why the function of the R288H mutant is impaired and what role this arginine (Arg) residue plays. In this study, we found that the apo-form of R288H PPARgamma mutant displays several altered conformational arrangements of the amino acid side chains in LBD: 1) the loss of a salt bridge between Arg288 and Glu295 leads to increased helix 3 movement; 2) closer proximity of Gln286 and His449 via a hydrogen bond, and closer proximity of Cys285 and Phe363 via hydrophobic interaction, stabilize the helix 3-helix 11 interaction; and 3) there is steric hindrance between Cys285/Gln286/Ser289/His449 and the flexible ligands 15d-PGJ2, 6-oxotetracosahexaenoic acid (6-oxoTHA), and 17-oxodocosahexaenoic acid (17-oxoDHA). These results suggest why Arg288 plays an important role in ligand binding and why the R288H mutation is disadvantageous for flexible ligand binding. | |||
Structural Insights into the Loss-of-Function R288H Mutant of Human PPARgamma.,Egawa D, Ogiso T, Nishikata K, Yamamoto K, Itoh T Biol Pharm Bull. 2021;44(9):1196-1201. doi: 10.1248/bpb.b21-00253. PMID:34471047<ref>PMID:34471047</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7e2o" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Peroxisome proliferator-activated receptor 3D structures|Peroxisome proliferator-activated receptor 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Egawa D]] | [[Category: Egawa D]] | ||
[[Category: Itoh T]] | [[Category: Itoh T]] | ||