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5u5l

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Revision as of 12:27, 23 September 2020

X-ray Crystal Structure of the PPARgamma Ligand Binding Domain in Complex with Rivoglitazone

Structural highlights

5u5l 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

Thiazolidinedione (TZD) compounds targeting the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) demonstrate unique benefits for the treatment of insulin resistance and type II diabetes. TZDs include rosiglitazone, pioglitazone and rivoglitazone, with the latter being the most potent. The TZDs are only marginally selective for the therapeutic target PPARgamma as they also activate PPARalpha and PPARdelta homologues to varying degrees, causing off-target effects. While crystal structures for TZD compounds in complex with PPARgamma are available, minimal structural information is available for TZDs bound to PPARalpha and PPARdelta. This paucity of structural information has hampered the determination of precise structural mechanisms involved in TZD selectivity between PPARs. To help address these questions molecular dynamic simulations were performed of rosiglitazone, pioglitazone and rivoglitazone in complex with PPARalpha, PPARdelta, and PPARgamma in order to better understand the mechanisms of PPAR selectivity. The simulations revealed that TZD interactions with residues Tyr314 and Phe318 of PPARalpha and residues Phe291 and Thr253 of PPARdelta as well as the omega loop, are key determinants of TZD receptor selectivity. Notably, in this study, we solve the first X-ray crystal structure of rivoglitazone bound to any PPAR. Rivoglitazone forms a unique hydrogen bond network with the residues of the PPARgamma co-activator binding surface (known as AF2) and makes more extensive contacts with helix 3 and the beta-sheet as compared to model TZD compounds such as rosiglitazone.

X-ray crystal structure of rivoglitazone bound to PPARgamma and PPAR subtype selectivity of TZDs.,Rajapaksha H, Bhatia H, Wegener K, Petrovsky N, Bruning JB Biochim Biophys Acta. 2017 Aug;1861(8):1981-1991. doi:, 10.1016/j.bbagen.2017.05.008. Epub 2017 May 9. PMID:28499821^[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
↑ Rajapaksha H, Bhatia H, Wegener K, Petrovsky N, Bruning JB. X-ray crystal structure of rivoglitazone bound to PPARgamma and PPAR subtype selectivity of TZDs. Biochim Biophys Acta. 2017 Aug;1861(8):1981-1991. doi:, 10.1016/j.bbagen.2017.05.008. Epub 2017 May 9. PMID:28499821 doi:http://dx.doi.org/10.1016/j.bbagen.2017.05.008

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/5u5l"

@@ Line 1: / Line 1: @@
 ==X-ray Crystal Structure of the PPARgamma Ligand Binding Domain in Complex with Rivoglitazone==
-<StructureSection load='5u5l' size='340' side='right' caption='[[5u5l]], [[Resolution|resolution]] 2.55&Aring;' scene=''>
+<StructureSection load='5u5l' size='340' side='right'caption='[[5u5l]], [[Resolution|resolution]] 2.55&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5u5l]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5U5L OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5U5L FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5u5l]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5U5L OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5U5L FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7VA:(5S)-5-({4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl)methoxy]phenyl}methyl)-1,3-thiazolidine-2,4-dione'>7VA</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7VA:(5S)-5-({4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl)methoxy]phenyl}methyl)-1,3-thiazolidine-2,4-dione'>7VA</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=5u5l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u5l OCA], [http://pdbe.org/5u5l PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5u5l RCSB], [http://www.ebi.ac.uk/pdbsum/5u5l PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5u5l ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5u5l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5u5l OCA], [http://pdbe.org/5u5l PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5u5l RCSB], [http://www.ebi.ac.uk/pdbsum/5u5l PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5u5l ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 20: / Line 20: @@
 </div>
 <div class="pdbe-citations 5u5l" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Peroxisome proliferator-activated receptor 3D structures|Peroxisome proliferator-activated receptor 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Large Structures]]
 [[Category: Bhatia, H]]
 [[Category: Bruning, J B]]

5u5l

From Proteopedia

Revision as of 12:27, 23 September 2020

X-ray Crystal Structure of the PPARgamma Ligand Binding Domain in Complex with Rivoglitazone

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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