4r06

From Proteopedia

(Difference between revisions)

Revision as of 09:09, 24 April 2019

Crystal Structure of SR2067 bound to PPARgamma

Structural highlights

4r06 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:	NR1C3, PPARG, PPARG_HUMAN (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

Synthetic full agonists of PPARgamma have been prescribed for the treatment of diabetes due to their ability to regulate glucose homeostasis and insulin sensitization. While the use of full agonists of PPARgamma has been hampered due to severe side effects, partial agonists have shown promise due to their decreased incidence of such side effects in preclinical models. No kinetic information has been forthcoming in regard to the mechanism of full versus partial agonism of PPARgamma to date. Here, we describe the discovery of a partial agonist, SR2067. A co-crystal structure obtained at 2.2 A resolution demonstrates that interactions with the beta-sheet are driven exclusively via hydrophobic interactions mediated through a naphthalene group, an observation that is unique from other partial agonists. Surface plasmon resonance revealed that SR2067 binds to the receptor with higher affinity (KD = 513 nM) as compared to that of full agonist rosiglitazone, yet it has a much slower off rate compared to that of rosiglitazone.

SR2067 Reveals a Unique Kinetic and Structural Signature for PPARgamma Partial Agonism.,van Marrewijk LM, Polyak SW, Hijnen M, Kuruvilla D, Chang MR, Shin Y, Kamenecka TM, Griffin PR, Bruning JB ACS Chem Biol. 2016 Jan 15;11(1):273-83. doi: 10.1021/acschembio.5b00580. Epub, 2015 Dec 3. PMID:26579553^[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
↑ van Marrewijk LM, Polyak SW, Hijnen M, Kuruvilla D, Chang MR, Shin Y, Kamenecka TM, Griffin PR, Bruning JB. SR2067 Reveals a Unique Kinetic and Structural Signature for PPARgamma Partial Agonism. ACS Chem Biol. 2016 Jan 15;11(1):273-83. doi: 10.1021/acschembio.5b00580. Epub, 2015 Dec 3. PMID:26579553 doi:http://dx.doi.org/10.1021/acschembio.5b00580

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/4r06"

@@ Line 1: / Line 1: @@
 ==Crystal Structure of SR2067 bound to PPARgamma==
-<StructureSection load='4r06' size='340' side='right' caption='[[4r06]], [[Resolution|resolution]] 2.22&Aring;' scene=''>
+<StructureSection load='4r06' size='340' side='right'caption='[[4r06]], [[Resolution|resolution]] 2.22&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4r06]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4R06 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4R06 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4r06]] 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=4R06 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4R06 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3E7:1-(NAPHTHALEN-1-YLSULFONYL)-N-[(1S)-1-PHENYLPROPYL]-1H-INDOLE-5-CARBOXAMIDE'>3E7</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=4r06 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r06 OCA], [http://pdbe.org/4r06 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4r06 RCSB], [http://www.ebi.ac.uk/pdbsum/4r06 PDBsum]</span></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NR1C3, PPARG, PPARG_HUMAN ([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=4r06 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r06 OCA], [http://pdbe.org/4r06 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4r06 RCSB], [http://www.ebi.ac.uk/pdbsum/4r06 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4r06 ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 19: / Line 21: @@
 </div>
 <div class="pdbe-citations 4r06" 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: Bruning, J B]]
 [[Category: Griffin, P R]]

4r06

From Proteopedia

Revision as of 09:09, 24 April 2019

Crystal Structure of SR2067 bound to PPARgamma

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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