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4pvu

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Revision as of 17:09, 4 January 2017

Crystal structure of the complex between PPARgamma-LBD and the R enantiomer of Mbx-102 (Metaglidasen)

Structural highlights

4pvu is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
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

Metaglidasen is a fibrate-like drug reported as a selective modulator of peroxisome proliferator-activated receptor gamma (PPARgamma), able to lower plasma glucose levels in the absence of the side effects typically observed with thiazolidinedione antidiabetic agents in current use. Herein we report an improved synthesis of metaglidasen's metabolically active form halofenic acid (R)-2 and that of its enantiomer (S)-2. The activity of the two stereoisomers was carefully examined on PPARalpha and PPARgamma subtypes. As expected, both showed partial agonist activity toward PPARgamma; the investigation of PPARalpha activity, however, led to unexpected results. In particular, (S)-2 was found to act as a partial agonist, whereas (R)-2 behaved as an antagonist. X-ray crystallographic studies with PPARgamma were carried out to gain more insight on the molecular-level interactions and to propose a binding mode. Given the adverse effects provoked by fibrate drugs on skeletal muscle function, we also investigated the capacity of (R)-2 and (S)-2 to block conductance of the skeletal muscle membrane chloride channel. The results showed a more beneficial profile for (R)-2, the activity of which on skeletal muscle function, however, should not be overlooked in the ongoing clinical trials studying its long-term effects.

On the Metabolically Active Form of Metaglidasen: Improved Synthesis and Investigation of Its Peculiar Activity on Peroxisome Proliferator-Activated Receptors and Skeletal Muscles.,Laghezza A, Montanari R, Lavecchia A, Piemontese L, Pochetti G, Iacobazzi V, Infantino V, Capelli D, De Bellis M, Liantonio A, Pierno S, Tortorella P, Conte Camerino D, Loiodice F ChemMedChem. 2015 Jan 29. doi: 10.1002/cmdc.201402462. PMID:25641779^[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
↑ Laghezza A, Montanari R, Lavecchia A, Piemontese L, Pochetti G, Iacobazzi V, Infantino V, Capelli D, De Bellis M, Liantonio A, Pierno S, Tortorella P, Conte Camerino D, Loiodice F. On the Metabolically Active Form of Metaglidasen: Improved Synthesis and Investigation of Its Peculiar Activity on Peroxisome Proliferator-Activated Receptors and Skeletal Muscles. ChemMedChem. 2015 Jan 29. doi: 10.1002/cmdc.201402462. PMID:25641779 doi:http://dx.doi.org/10.1002/cmdc.201402462

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/4pvu"

@@ Line 1: / Line 1: @@
 ==Crystal structure of the complex between PPARgamma-LBD and the R enantiomer of Mbx-102 (Metaglidasen)==
 <StructureSection load='4pvu' size='340' side='right' caption='[[4pvu]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
@@ Line 4: / Line 5: @@
 <table><tr><td colspan='2'>[[4pvu]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4PVU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4PVU FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MGZ:(2R)-(4-CHLOROPHENYL)[3-(TRIFLUOROMETHYL)PHENOXY]ETHANOIC+ACID'>MGZ</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=4pvu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pvu OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4pvu RCSB], [http://www.ebi.ac.uk/pdbsum/4pvu 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=4pvu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pvu OCA], [http://pdbe.org/4pvu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4pvu RCSB], [http://www.ebi.ac.uk/pdbsum/4pvu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4pvu ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 18: / Line 19: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4pvu" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

4pvu

From Proteopedia

Revision as of 17:09, 4 January 2017

Crystal structure of the complex between PPARgamma-LBD and the R enantiomer of Mbx-102 (Metaglidasen)

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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