3d6d

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Template:STRUCTURE 3d6d

Crystal Structure of the complex between PPARgamma LBD and the LT175(R-enantiomer)Crystal Structure of the complex between PPARgamma LBD and the LT175(R-enantiomer)

Template:ABSTRACT PUBMED 19053776

DiseaseDisease

[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.

FunctionFunction

[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]

About this StructureAbout this Structure

3d6d is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.

See AlsoSee Also

ReferenceReference

[xtra 1][xtra 2][xtra 3][xtra 4]

  1. ↑ Montanari R, Saccoccia F, Scotti E, Crestani M, Godio C, Gilardi F, Loiodice F, Fracchiolla G, Laghezza A, Tortorella P, Lavecchia A, Novellino E, Mazza F, Aschi M, Pochetti G. Crystal structure of the peroxisome proliferator-activated receptor gamma (PPARgamma) ligand binding domain complexed with a novel partial agonist: a new region of the hydrophobic pocket could be exploited for drug design. J Med Chem. 2008 Dec 25;51(24):7768-76. PMID:19053776 doi:10.1021/jm800733h
  2. ↑ 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
  3. ↑ Bruning JB, Chalmers MJ, Prasad S, Busby SA, Kamenecka TM, He Y, Nettles KW, Griffin PR. Partial agonists activate PPARgamma using a helix 12 independent mechanism. Structure. 2007 Oct;15(10):1258-71. PMID:17937915 doi:http://dx.doi.org/10.1016/j.str.2007.07.014
  4. ↑ Gampe RT Jr, Montana VG, Lambert MH, Miller AB, Bledsoe RK, Milburn MV, Kliewer SA, Willson TM, Xu HE. Asymmetry in the PPARgamma/RXRalpha crystal structure reveals the molecular basis of heterodimerization among nuclear receptors. Mol Cell. 2000 Mar;5(3):545-55. PMID:10882139
  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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

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