4fgy

Identification of a unique PPAR ligand with an unexpected binding mode and antibetic activity

spinqualitylabelsall models 4fgy, resolution 2.84Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4fgy 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: 0W3 Gene: NR1C3, PPARG (HUMAN) Activity: Histone acetyltransferase, with EC number 2.3.1.48 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. 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. 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. [NCOA1_HUMAN] Note=A chromosomal aberration involving NCOA1 is a cause of rhabdomyosarcoma. Translocation t(2;2)(q35;p23) with PAX3 generates the NCOA1-PAX3 oncogene consisting of the N-terminus part of PAX3 and the C-terminus part of NCOA1. The fusion protein acts as a transcriptional activator. Rhabdomyosarcoma is the most common soft tissue carcinoma in childhood, representing 5-8% of all malignancies in children. 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. [NCOA1_HUMAN] Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. Involved in the coactivation of different nuclear receptors, such as for steroids (PGR, GR and ER), retinoids (RXRs), thyroid hormone (TRs) and prostanoids (PPARs). Also involved in coactivation mediated by STAT3, STAT5A, STAT5B and STAT6 transcription factors. Displays histone acetyltransferase activity toward H3 and H4; the relevance of such activity remains however unclear. Plays a central role in creating multisubunit coactivator complexes that act via remodeling of chromatin, and possibly acts by participating in both chromatin remodeling and recruitment of general transcription factors. Required with NCOA2 to control energy balance between white and brown adipose tissues. Required for mediating steroid hormone response. Isoform 2 has a higher thyroid hormone-dependent transactivation activity than isoform 1 and isoform 3. Publication Abstract from PubMed AIMS/HYPOTHESIS: Existing thiazolidinedione (TZD) drugs for diabetes have severe side effects. The aim of this study is to develop alternative peroxisome proliferator-activated receptor gamma (PPARgamma) ligands that retain the benefits in improving insulin resistance but with reduced side effects. METHODS: We used AlphaScreen assay to screen for new PPARgamma ligands from compound libraries. In vitro biochemical binding affinity assay and in vivo cell-based reporter assay were used to validate ionomycin as a partial ligand of PPARgamma. A mouse model of diabetes was used to assess the effects of ionomycin in improving insulin sensitivity. Crystal structure of PPARgamma complexed with ionomycin revealed the unique binding mode of ionomycin, which elucidated the molecular mechanisms allowing the discrimination of ionomycin from TZDs. RESULTS: We found that the antibiotic ionomycin is a novel modulating ligand for PPARgamma. Both the transactivation and binding activity of PPARgamma by ionomycin can be blocked by PPARgamma specific antagonist GW9662. Ionomycin interacts with the PPARgamma ligand-binding domain in a unique binding mode with properties and epitopes distinct from those of TZD drugs. Ionomycin treatment effectively improved hyperglycaemia and insulin resistance, but had reduced side effects compared with TZDs in the mouse model of diabetes. In addition, ionomycin effectively blocked the phosphorylation of PPARgamma at Ser273 by cyclin-dependent kinase 5 both in vitro and in vivo. CONCLUSIONS/INTERPRETATION: Our studies suggest that ionomycin may represent a unique template for designing novel PPARgamma ligands with advantages over current TZD drugs. Identification of the antibiotic ionomycin as an unexpected peroxisome proliferator-activated receptor gamma (PPARgamma) ligand with a unique binding mode and effective glucose-lowering activity in a mouse model of diabetes.,Zheng W, Feng X, Qiu L, Pan Z, Wang R, Lin S, Hou D, Jin L, Li Y Diabetologia. 2013 Feb;56(2):401-11. doi: 10.1007/s00125-012-2777-9. Epub 2012, Nov 23. PMID:23178929 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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