6k0t: Difference between revisions
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==Crystal Structure of PPARgamma Ligand Binding Domain in complex with dibenzooxepine derivative compound-17== | |||
<StructureSection load='6k0t' size='340' side='right'caption='[[6k0t]], [[Resolution|resolution]] 1.84Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6k0t]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6K0T OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6K0T FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CTU:3-[(1~{E})-1-[8-[(8-chloranyl-2-cyclopropyl-imidazo[1,2-a]pyridin-3-yl)methyl]-3-fluoranyl-6~{H}-benzo[c][1]benzoxepin-11-ylidene]ethyl]-4~{H}-1,2,4-oxadiazol-5-one'>CTU</scene></td></tr> | |||
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</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=6k0t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6k0t OCA], [http://pdbe.org/6k0t PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6k0t RCSB], [http://www.ebi.ac.uk/pdbsum/6k0t PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6k0t 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 == | |||
We previously identified dibenzooxepine derivative 1 as a potent PPARgamma ligand with a unique binding mode owing to its non-thiazolidinedione scaffold. However, while 1 showed remarkably potent MKN-45 gastric cancer cell aggregation activity, an indicator of cancer differentiation-inducing activity induced by PPARgamma activation, we recognized that 1 was metabolically unstable. In the present study, we identified a metabolically soft spot, and successfully discovered 3-fluoro dibenzooxepine derivative 9 with better metabolic stability. Further optimization provided imidazo[1,2-a]pyridine derivative 17, which showed potent MKN-45 gastric cancer cell aggregation activity and excellent PK profiles compared with 9. Compound 17 exerted a growth inhibitory effect on AsPC-1/AG1 pancreatic tumor in mice. Furthermore, the decrease in the hematocrit (an indicator of localized edema, a serious adverse effect of PPARgamma ligands) was tolerable even with oral administration at 200mg/kg in healthy mice. | |||
Development of a novel class of peroxisome proliferator-activated receptor (PPAR) gamma ligands as an anticancer agent with a unique binding mode based on a non-thiazolidinedione scaffold.,Yamamoto K, Tamura T, Nakamura R, Hosoe S, Matsubara M, Nagata K, Kodaira H, Uemori T, Takahashi Y, Suzuki M, Saito JI, Ueno K, Shuto S Bioorg Med Chem. 2019 Nov 15;27(22):115122. doi: 10.1016/j.bmc.2019.115122. Epub , 2019 Sep 16. PMID:31623970<ref>PMID:31623970</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6k0t" style="background-color:#fffaf0;"></div> | ||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Saito, J]] | |||
[[Category: Suzuki, M]] | [[Category: Suzuki, M]] | ||
[[Category: Takahashi, Y]] | [[Category: Takahashi, Y]] | ||
[[Category: | [[Category: Yamamoto, K]] | ||
[[Category: Cancer]] | |||
[[Category: Ligand binding domain]] | |||
[[Category: Nuclear protein]] | |||
[[Category: Pparg modulator]] | |||
[[Category: Ppargamma]] | |||
