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3ty0

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Revision as of 22:31, 5 August 2016

Structure of PPARgamma ligand binding domain in complex with (R)-5-(3-((3-(6-methoxybenzo[d]isoxazol-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)-5-methyloxazolidine-2,4-dione

Structural highlights

3ty0 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	PPARG, NR1C3 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[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: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.^[1] Defects in PPARG are the cause of familial partial lipodystrophy type 3 (FPLD3) [MIM: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.^[2] ^[3] Genetic variations in PPARG can be associated with susceptibility to glioma type 1 (GLM1) [MIM: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

[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.^[4] ^[5] ^[6]

Publication Abstract from PubMed

A series of benzimidazolone carboxylic acids and oxazolidinediones were designed and synthesized in search of selective PPARgamma modulators (SPPARgammaMs) as potential therapeutic agents for the treatment of type II diabetes mellitus (T2DM) with potentially improved safety profiles relative to rosiglitazone and pioglitazone, the currently marketed PPARgamma full agonist drugs. Structure-activity relationships of these potent and highly selective SPPARgammaMs were studied with a focus on their unique profiles as partial agonists or modulators. A variety of methods, such as X-ray crystallographic analysis, PPARgamma transactivation co-activator profiling, gene expression profiling and mutagenesis studies, were employed to reveal the differential interactions of these new analogs with the PPARgamma receptor in comparison to full agonists. In rodent models of T2DM, benzimidazolone analogs such as (5R)-5-(3-{[3-(5-methoxybenzisoxazol-3-yl)benzimidazol-1-yl]methyl}phenyl) -5-methyloxazolidinedione (51) demonstrated equivalent efficacy to rosiglitazone. Side effects, such as fluid retention and heart weight gain associated with PPARgamma full agonists, were diminished with 51 in comparison to rosiglitazone based on studies in two independent animal models.

Benzimidazolones - A New Class of Selective Peroxisome Proliferator-Activated Receptor Gamma (PPARg) Modulators.,Liu W, Lau F, Liu K, Wood HB, Zhou G, Chen Y, Li Y, Akiyama TE, Castriota G, Einstein M, Wang C, McCann ME, Doebber TW, Wu M, Chang CH, McNamara L, McKeever B, Mosley RT, Berger J, Meinke PT J Med Chem. 2011 Nov 9. PMID:22070604^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Ristow M, Muller-Wieland D, Pfeiffer A, Krone W, Kahn CR. Obesity associated with a mutation in a genetic regulator of adipocyte differentiation. N Engl J Med. 1998 Oct 1;339(14):953-9. PMID:9753710 doi:10.1056/NEJM199810013391403
↑ Hegele RA, Cao H, Frankowski C, Mathews ST, Leff T. PPARG F388L, a transactivation-deficient mutant, in familial partial lipodystrophy. Diabetes. 2002 Dec;51(12):3586-90. PMID:12453919
↑ Agarwal AK, Garg A. A novel heterozygous mutation in peroxisome proliferator-activated receptor-gamma gene in a patient with familial partial lipodystrophy. J Clin Endocrinol Metab. 2002 Jan;87(1):408-11. PMID:11788685
↑ Mukherjee R, Jow L, Croston GE, Paterniti JR Jr. Identification, characterization, and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPARgamma2 versus PPARgamma1 and activation with retinoid X receptor agonists and antagonists. J Biol Chem. 1997 Mar 21;272(12):8071-6. PMID:9065481
↑ Yin Y, Yuan H, Wang C, Pattabiraman N, Rao M, Pestell RG, Glazer RI. 3-phosphoinositide-dependent protein kinase-1 activates the peroxisome proliferator-activated receptor-gamma and promotes adipocyte differentiation. Mol Endocrinol. 2006 Feb;20(2):268-78. Epub 2005 Sep 8. PMID:16150867 doi:10.1210/me.2005-0197
↑ Park SH, Choi HJ, Yang H, Do KH, Kim J, Lee DW, Moon Y. Endoplasmic reticulum stress-activated C/EBP homologous protein enhances nuclear factor-kappaB signals via repression of peroxisome proliferator-activated receptor gamma. J Biol Chem. 2010 Nov 12;285(46):35330-9. doi: 10.1074/jbc.M110.136259. Epub 2010, Sep 9. PMID:20829347 doi:10.1074/jbc.M110.136259
↑ Liu W, Lau F, Liu K, Wood HB, Zhou G, Chen Y, Li Y, Akiyama TE, Castriota G, Einstein M, Wang C, McCann ME, Doebber TW, Wu M, Chang CH, McNamara L, McKeever B, Mosley RT, Berger J, Meinke PT. Benzimidazolones - A New Class of Selective Peroxisome Proliferator-Activated Receptor Gamma (PPARg) Modulators. J Med Chem. 2011 Nov 9. PMID:22070604 doi:10.1021/jm201061j

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3ty0"

@@ Line 1: / Line 1: @@
 ==Structure of PPARgamma ligand binding domain in complex with (R)-5-(3-((3-(6-methoxybenzo[d]isoxazol-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)-5-methyloxazolidine-2,4-dione==
 <StructureSection load='3ty0' size='340' side='right' caption='[[3ty0]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3ty0]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3TY0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3TY0 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3ty0]] is a 2 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=3TY0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3TY0 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=082:(5R)-5-(3-{[3-(6-METHOXY-1,2-BENZOXAZOL-3-YL)-2-OXO-2,3-DIHYDRO-1H-BENZIMIDAZOL-1-YL]METHYL}PHENYL)-5-METHYL-1,3-OXAZOLIDINE-2,4-DIONE'>082</scene></td></tr>
-<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 Homo sapiens])</td></tr>
+<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>
-<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=3ty0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ty0 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3ty0 RCSB], [http://www.ebi.ac.uk/pdbsum/3ty0 PDBsum]</span></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=3ty0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ty0 OCA], [http://pdbe.org/3ty0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3ty0 RCSB], [http://www.ebi.ac.uk/pdbsum/3ty0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3ty0 ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 19: / Line 20: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 3ty0" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Liu, W]]
 [[Category: McKeever, B]]

3ty0

From Proteopedia

Revision as of 22:31, 5 August 2016

Structure of PPARgamma ligand binding domain in complex with (R)-5-(3-((3-(6-methoxybenzo[d]isoxazol-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)phenyl)-5-methyloxazolidine-2,4-dione

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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