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6k0t

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Current revision (08:17, 6 November 2019) (edit) (undo)
 
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'''Unreleased structure'''
 
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The entry 6k0t is ON HOLD until Paper Publication
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==Crystal Structure of PPARgamma Ligand Binding Domain in complex with dibenzooxepine derivative compound-17==
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<StructureSection load='6k0t' size='340' side='right'caption='[[6k0t]], [[Resolution|resolution]] 1.84&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[6k0t]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. 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>
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</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>
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<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>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PPARG, NR1C3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<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>
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</table>
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== Disease ==
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[[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.
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== Function ==
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[[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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Authors: Suzuki, M., Yamamoto, K., Takahashi, Y., Saito, J.
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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>
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Description: Crystal Structure of PPARgamma Ligand Binding Domain in complex with dibenzooxepine derivative compound-17
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Yamamoto, K]]
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<div class="pdbe-citations 6k0t" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Human]]
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[[Category: Large Structures]]
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[[Category: Saito, J]]
[[Category: Suzuki, M]]
[[Category: Suzuki, M]]
[[Category: Takahashi, Y]]
[[Category: Takahashi, Y]]
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[[Category: Saito, J]]
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[[Category: Yamamoto, K]]
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[[Category: Cancer]]
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[[Category: Ligand binding domain]]
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[[Category: Nuclear protein]]
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[[Category: Pparg modulator]]
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[[Category: Ppargamma]]

Current revision

Crystal Structure of PPARgamma Ligand Binding Domain in complex with dibenzooxepine derivative compound-17

PDB ID 6k0t

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