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2i4z

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Revision as of 02:31, 12 September 2015

Crystal structure of the complex between PPARgamma and the partial agonist LT127 (ureidofibrate derivative). This structure has been obtained from crystals soaked for 6 hours.

Structural highlights

2i4z 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:
Related:	1prg, 2prg, 4prg, 2i4j
Gene:	PPARG, NR1C3 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum

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]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

The peroxisome proliferator-activated receptors (PPARs) are transcriptional regulators of glucose and lipid metabolism. They are activated by natural ligands, such as fatty acids, and are also targets of synthetic antidiabetic and hypolipidemic drugs. By using cell-based reporter assays, we studied the transactivation activity of two enantiomeric ureidofibrate-like derivatives. In particular, we show that the R-enantiomer, (R)-1, is a full agonist of PPARgamma, whereas the S-enantiomer, (S)-1, is a less potent partial agonist. Most importantly, we report the x-ray crystal structures of the PPARgamma ligand binding domain complexed with the R- and the S-enantiomer, respectively. The analysis of the two crystal structures shows that the different degree of stabilization of the helix 12 induced by the ligand determines its behavior as full or partial agonist. Another crystal structure of the PPARgamma.(S)-1 complex, only differing in the soaking time of the ligand, is also presented. The comparison of the two structures of the complexes with the partial agonist reveals significant differences and is suggestive of the possible coexistence in solution of transcriptionally active and inactive forms of helix 12 in the presence of a partial agonist. Mutation analysis confirms the importance of Leu(465), Leu(469), and Ile(472) in the activation by (R)-1 and underscores the key role of Gln(286) in the PPARgamma activity.

Insights into the mechanism of partial agonism: crystal structures of the peroxisome proliferator-activated receptor gamma ligand-binding domain in the complex with two enantiomeric ligands.,Pochetti G, Godio C, Mitro N, Caruso D, Galmozzi A, Scurati S, Loiodice F, Fracchiolla G, Tortorella P, Laghezza A, Lavecchia A, Novellino E, Mazza F, Crestani M J Biol Chem. 2007 Jun 8;282(23):17314-24. Epub 2007 Apr 2. PMID:17403688^[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
↑ Pochetti G, Godio C, Mitro N, Caruso D, Galmozzi A, Scurati S, Loiodice F, Fracchiolla G, Tortorella P, Laghezza A, Lavecchia A, Novellino E, Mazza F, Crestani M. Insights into the mechanism of partial agonism: crystal structures of the peroxisome proliferator-activated receptor gamma ligand-binding domain in the complex with two enantiomeric ligands. J Biol Chem. 2007 Jun 8;282(23):17314-24. Epub 2007 Apr 2. PMID:17403688 doi:10.1074/jbc.M702316200

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2i4z"

Categories: Human | Mazza, F | Pochetti, G | Bundle of alpha-helices and a small four-stranded beta-sheet | Transcription

@@ Line 2: / Line 2: @@
 <StructureSection load='2i4z' size='340' side='right' caption='[[2i4z]], [[Resolution|resolution]] 2.25&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2i4z]] 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=2I4Z OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2I4Z FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2i4z]] 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=2I4Z OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2I4Z FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DRH:(2S)-2-(4-{2-[1,3-BENZOXAZOL-2-YL(HEPTYL)AMINO]ETHYL}PHENOXY)-2-METHYLBUTANOIC+ACID'>DRH</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1prg|1prg]], [[2prg|2prg]], [[4prg|4prg]], [[2i4j|2i4j]]</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=2i4z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2i4z OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2i4z RCSB], [http://www.ebi.ac.uk/pdbsum/2i4z 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=2i4z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2i4z OCA], [http://pdbe.org/2i4z PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2i4z RCSB], [http://www.ebi.ac.uk/pdbsum/2i4z PDBsum]</span></td></tr>
 </table>
 == Disease ==
@@ Line 30: / Line 30: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 2i4z" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 37: / Line 38: @@
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Mazza, F]]
 [[Category: Pochetti, G]]
 [[Category: Bundle of alpha-helices and a small four-stranded beta-sheet]]
 [[Category: Transcription]]

2i4z

From Proteopedia

Revision as of 02:31, 12 September 2015

Crystal structure of the complex between PPARgamma and the partial agonist LT127 (ureidofibrate derivative). This structure has been obtained from crystals soaked for 6 hours.

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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