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4yt1

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Revision as of 07:01, 12 June 2019

Human PPAR Gamma Ligand Binding Domain in complex with a Gammma Selective Synthetic Partial Agonist MEKT76

Structural highlights

4yt1 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

In the course of studies directed toward the creation of human peroxisome proliferator-activated receptor gamma (hPPARgamma) partial agonists, we designed and synthesized benzylsulfonylaminocarbonyl derivative (3) by structural modification of our reported hPPARgamma partial agonist 2. Co-crystallization of 3 with the hPPARgamma ligand-binding domain (LBD) afforded a homodimeric complex in which one of the LBDs adopts a fully active structure without bound 3, while the other LBD exhibits a non-fully active structure containing one molecule of bound 3. Interestingly, 2 and 3 are structurally similar, but bind to hPPARgamma LBD in distinct conformations, that is, the sulfonylaminocarbonyl moiety of bound 3 is directed at 180 degrees away from that of bound 2. These results support our previous proposal that the hPPARgamma LBD has multiple binding points that can be utilized to accommodate structurally flexible hPPAR ligands.

Peroxisome proliferator-activated receptor gamma (PPARgamma) has multiple binding points that accommodate ligands in various conformations: Structurally similar PPARgamma partial agonists bind to PPARgamma LBD in different conformations.,Ohashi M, Gamo K, Oyama T, Miyachi H Bioorg Med Chem Lett. 2015 Jul 15;25(14):2758-62. doi:, 10.1016/j.bmcl.2015.05.025. Epub 2015 May 22. PMID:26025876^[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
↑ Ohashi M, Gamo K, Oyama T, Miyachi H. Peroxisome proliferator-activated receptor gamma (PPARgamma) has multiple binding points that accommodate ligands in various conformations: Structurally similar PPARgamma partial agonists bind to PPARgamma LBD in different conformations. Bioorg Med Chem Lett. 2015 Jul 15;25(14):2758-62. doi:, 10.1016/j.bmcl.2015.05.025. Epub 2015 May 22. PMID:26025876 doi:http://dx.doi.org/10.1016/j.bmcl.2015.05.025

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4yt1"

@@ Line 1: / Line 1: @@
 ==Human PPAR Gamma Ligand Binding Domain in complex with a Gammma Selective Synthetic Partial Agonist MEKT76==
-<StructureSection load='4yt1' size='340' side='right' caption='[[4yt1]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
+<StructureSection load='4yt1' size='340' side='right'caption='[[4yt1]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4yt1]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YT1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4YT1 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4yt1]] 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=4YT1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4YT1 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=JJB:N-(BENZYLSULFONYL)-4-PROPOXY-3-({[4-(PYRIMIDIN-2-YL)BENZOYL]AMINO}METHYL)BENZAMIDE'>JJB</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=4yt1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4yt1 OCA], [http://pdbe.org/4yt1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4yt1 RCSB], [http://www.ebi.ac.uk/pdbsum/4yt1 PDBsum]</span></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=4yt1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4yt1 OCA], [http://pdbe.org/4yt1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4yt1 RCSB], [http://www.ebi.ac.uk/pdbsum/4yt1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4yt1 ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 20: / Line 21: @@
 </div>
 <div class="pdbe-citations 4yt1" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Peroxisome Proliferator-Activated Receptors|Peroxisome Proliferator-Activated Receptors]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Kusunoki, M]]
 [[Category: Miyachi, H]]

4yt1

From Proteopedia

Revision as of 07:01, 12 June 2019

Human PPAR Gamma Ligand Binding Domain in complex with a Gammma Selective Synthetic Partial Agonist MEKT76

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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