View source for 6md1


==Crystal Structure of Human PPARgamma Ligand Binding Domain in Complex with GW9662 and Oleic acid==
<StructureSection load='6md1' size='340' side='right' caption='[[6md1]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6md1]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MD1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MD1 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GW9:2-CHLORO-5-NITRO-N-PHENYLBENZAMIDE'>GW9</scene>, <scene name='pdbligand=OLA:OLEIC+ACID'>OLA</scene></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=6md1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6md1 OCA], [http://pdbe.org/6md1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6md1 RCSB], [http://www.ebi.ac.uk/pdbsum/6md1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6md1 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 ==
Crystal structures of peroxisome proliferator-activated receptor gamma (PPARgamma) have revealed overlapping binding modes for synthetic and natural/endogenous ligands, indicating competition for the orthosteric pocket. Here we show that cobinding of a synthetic ligand to the orthosteric pocket can push natural and endogenous PPARgamma ligands (fatty acids) out of the orthosteric pocket towards an alternate ligand-binding site near the functionally important omega (Omega)-loop. X-ray crystallography, NMR spectroscopy, all-atom molecular dynamics simulations, and mutagenesis coupled to quantitative biochemical functional and cellular assays reveal that synthetic ligand and fatty acid cobinding can form a 'ligand link' to the Omega-loop and synergistically affect the structure and function of PPARgamma. These findings contribute to a growing body of evidence indicating ligand binding to nuclear receptors can be more complex than the classical one-for-one orthosteric exchange of a natural or endogenous ligand with a synthetic ligand.

Cooperative cobinding of synthetic and natural ligands to the nuclear receptor PPARgamma.,Shang J, Brust R, Mosure SA, Bass J, Munoz-Tello P, Lin H, Hughes TS, Tang M, Ge Q, Kamenekca TM, Kojetin DJ Elife. 2018 Dec 21;7. pii: 43320. doi: 10.7554/eLife.43320. PMID:30575522<ref>PMID:30575522</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6md1" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Kojetin, D J]]
[[Category: Shang, J]]
[[Category: Drug design]]
[[Category: Nuclear receptor]]
[[Category: Therapeutic target]]
[[Category: Transcription]]
[[Category: Tzd]]