| Structural highlights
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 major therapeutic target for the treatment of type 2 diabetes. However, the use of PPARgamma-targeted drugs, such as rosiglitazone and pioglitazone, is limited owing to serious side effects caused by classical agonism. Using a rational drug discovery approach, we recently developed SB1495, a novel reversible covalent inhibitor of the cyclin-dependent kinase 5 (Cdk5)-mediated phosphorylation of PPARgamma at Ser245, a key factor in the insulin-sensitizing effect of PPARgamma-targeted drugs. In this study, we report the crystal structures of PPARgamma in complex with SB1495 and its enantiomeric analogue SB1494, which rarely exhibits inhibitory activity, to visualize the mechanistic basis for their distinct activities. SB1495 occupies the Arm3 region near the Omega loop of the PPARgamma ligand-binding domain, whereas its enantiomeric analogue SB1494 binds to the Arm2 region. In addition, the piperazine moiety of SB1495 directly pushes the helix H2', resulting in the stabilization of the Omega loop just behind the helix H2'. Our results may contribute to the development of a new generation of antidiabetic drugs that selectively block PPARgamma phosphorylation without classical agonism.
Structural basis for the inhibitory effects of a novel reversible covalent ligand on PPARgamma phosphorylation.,Jang JY, Kim H, Kim HJ, Suh SW, Park SB, Han BW Sci Rep. 2019 Aug 1;9(1):11168. doi: 10.1038/s41598-019-47672-w. PMID:31371757[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Jang JY, Kim H, Kim HJ, Suh SW, Park SB, Han BW. Structural basis for the inhibitory effects of a novel reversible covalent ligand on PPARgamma phosphorylation. Sci Rep. 2019 Aug 1;9(1):11168. doi: 10.1038/s41598-019-47672-w. PMID:31371757 doi:http://dx.doi.org/10.1038/s41598-019-47672-w
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