6ms7

From Proteopedia

(Difference between revisions)

Revision as of 07:13, 15 April 2020

Peroxisome proliferator-activated receptor gamma ligand binding domain in complex with a novel selective PPAR-gamma modulator VSP-77

Structural highlights

6ms7 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

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a key regulator of glucose homeostasis and lipid metabolism, and an important target for the development of modern anti-diabetic drugs. However, current PPARgamma-targeting anti-diabetic drugs such as classical thiazolidinediones (TZDs) are associated with undesirable side effects. To address this concern, we here describe the structure-based design, synthesis, identification and detailed in vitro and in vivo characterization of a novel, decanoic acid (DA)-based and selective PPARgamma modulator (SPPARgammaM), VSP-77, especially (S)-VSP-77, as the potential "hit" for the development of improved and safer anti-diabetic therapeutics. We have also determined the co-crystal structure of the PPARgamma ligand-binding domain (LBD) in complex with two molecules of (S)-VSP-77, which reveal a previously undisclosed allosteric binding mode. Overall, these findings not only demonstrate the therapeutic advantage of (S)-VSP-77 over current TZD drugs and representative partial agonist INT131, but also provide a rational basis for the development of future SPPARgammaMs as safe and highly efficacious anti-diabetic drugs.

Identification and structural insight of an effective PPARgamma modulator with improved therapeutic index for anti-diabetic drug discovery.,Jiang H, Zhou XE, Shi J, Zhou Z, Zhao G, Zhang X, Sun Y, Suino-Powell K, Ma L, Gao H, Yu X, Li J, Li J, Melcher K, Xu HE, Yi W Chem Sci. 2020 Jan 21;11(8):2260-2268. doi: 10.1039/c9sc05487a. eCollection 2020 , Feb 28. PMID:32190280^[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
↑ Jiang H, Zhou XE, Shi J, Zhou Z, Zhao G, Zhang X, Sun Y, Suino-Powell K, Ma L, Gao H, Yu X, Li J, Li J, Melcher K, Xu HE, Yi W. Identification and structural insight of an effective PPARgamma modulator with improved therapeutic index for anti-diabetic drug discovery. Chem Sci. 2020 Jan 21;11(8):2260-2268. doi: 10.1039/c9sc05487a. eCollection 2020 , Feb 28. PMID:32190280 doi:http://dx.doi.org/10.1039/c9sc05487a

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/6ms7"

@@ Line 3: / Line 3: @@
 <StructureSection load='6ms7' size='340' side='right'caption='[[6ms7]], [[Resolution|resolution]] 1.43&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6ms7]] 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=6MS7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6MS7 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6ms7]] 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=6MS7 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6MS7 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=V77:{[(1S)-1-(4-chlorophenyl)octyl]oxy}acetic+acid'>V77</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=V77:{[(1S)-1-(4-chlorophenyl)octyl]oxy}acetic+acid'>V77</scene></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=6ms7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ms7 OCA], [http://pdbe.org/6ms7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ms7 RCSB], [http://www.ebi.ac.uk/pdbsum/6ms7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ms7 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=6ms7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ms7 OCA], [http://pdbe.org/6ms7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ms7 RCSB], [http://www.ebi.ac.uk/pdbsum/6ms7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ms7 ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 12: / Line 12: @@
 == Function ==
 [[http://www.uniprot.org/uniprot/PPARG_HUMAN 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.<ref>PMID:9065481</ref> <ref>PMID:16150867</ref> <ref>PMID:20829347</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Peroxisome proliferator-activated receptor gamma (PPARgamma) is a key regulator of glucose homeostasis and lipid metabolism, and an important target for the development of modern anti-diabetic drugs. However, current PPARgamma-targeting anti-diabetic drugs such as classical thiazolidinediones (TZDs) are associated with undesirable side effects. To address this concern, we here describe the structure-based design, synthesis, identification and detailed in vitro and in vivo characterization of a novel, decanoic acid (DA)-based and selective PPARgamma modulator (SPPARgammaM), VSP-77, especially (S)-VSP-77, as the potential "hit" for the development of improved and safer anti-diabetic therapeutics. We have also determined the co-crystal structure of the PPARgamma ligand-binding domain (LBD) in complex with two molecules of (S)-VSP-77, which reveal a previously undisclosed allosteric binding mode. Overall, these findings not only demonstrate the therapeutic advantage of (S)-VSP-77 over current TZD drugs and representative partial agonist INT131, but also provide a rational basis for the development of future SPPARgammaMs as safe and highly efficacious anti-diabetic drugs.
+Identification and structural insight of an effective PPARgamma modulator with improved therapeutic index for anti-diabetic drug discovery.,Jiang H, Zhou XE, Shi J, Zhou Z, Zhao G, Zhang X, Sun Y, Suino-Powell K, Ma L, Gao H, Yu X, Li J, Li J, Melcher K, Xu HE, Yi W Chem Sci. 2020 Jan 21;11(8):2260-2268. doi: 10.1039/c9sc05487a. eCollection 2020 , Feb 28. PMID:32190280<ref>PMID:32190280</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 6ms7" style="background-color:#fffaf0;"></div>
 ==See Also==

6ms7

From Proteopedia

Revision as of 07:13, 15 April 2020

Peroxisome proliferator-activated receptor gamma ligand binding domain in complex with a novel selective PPAR-gamma modulator VSP-77

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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