Selective targeting of PPARγ by the natural product chelerythrine with a unique binding mode and improved antidiabetic potency

Scientific Reports

Volumn 5, Issue , 2015, Pages

  Zheng, Weili ^a   Qiu, Lin ^a   Wang, Rui ^a   Feng, Xuhui ^a   Han, Yaping ^a   Zhu, Yanlin ^a   Chen, Dezhou ^a   Liu, Yijie ^a   Jin, Lihua ^a   Li, Yong ^a  

^a XIAMEN UNIVERSITY   (China)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIDIABETIC AGENT; BENZOPHENANTHRIDINE DERIVATIVE; BIOLOGICAL PRODUCT; CHELERYTHRINE; CYCLIN DEPENDENT KINASE 5; GLUCOSE; LIGAND; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PROTEIN BINDING;

ADIPOGENESIS; AGONISTS; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMISTRY; CONFORMATION; DIABETES MELLITUS, TYPE 2; DISEASE MODEL; DRUG EFFECTS; EXPERIMENTAL DIABETES MELLITUS; INSULIN RESISTANCE; KINETICS; METABOLISM; MOLECULAR MODEL; MOLECULARLY TARGETED THERAPY; MOUSE; PHOSPHORYLATION; WEIGHT GAIN;

ADIPOGENESIS; ANIMALS; BENZOPHENANTHRIDINES; BIOLOGICAL PRODUCTS; CYCLIN-DEPENDENT KINASE 5; DIABETES MELLITUS, EXPERIMENTAL; DIABETES MELLITUS, TYPE 2; DISEASE MODELS, ANIMAL; GLUCOSE; HYPOGLYCEMIC AGENTS; INSULIN RESISTANCE; KINETICS; LIGANDS; MICE; MODELS, MOLECULAR; MOLECULAR CONFORMATION; MOLECULAR TARGETED THERAPY; PHOSPHORYLATION; PPAR GAMMA; PROTEIN BINDING; WEIGHT GAIN;

EID: 84937484796     PISSN: None     EISSN: 20452322     Source Type: Journal    
DOI: 10.1038/srep12222     Document Type: Article

References (37)

1. Pan, Y., Tsai, C. J., Ma, B. & Nussinov, R. How do transcription factors select specific binding sites in the genome? Nat Struct Mol Biol 16, 1118-1120 (2009).
2. Khorasanizadeh, S. & Rastinejad, F. Nuclear-receptor interactions on DNA-response elements. Trends Biochem Sci 26, 384-390 (2001).
3. Dilworth, F. J. & Chambon, P. Nuclear receptors coordinate the activities of chromatin remodeling complexes and coactivators to facilitate initiation of transcription. Oncogene 20, 3047-3054 (2001).
4. Burris, T. P. et al. Nuclear receptors and their selective pharmacologic modulators. Pharmacol Rev 65, 710-778 (2013).
5. Woldt, E. et al. The nuclear hormone receptor PPAR? counteracts vascular calcification by inhibiting Wnt5a signalling in vascular smooth muscle cells. Nat Commun 3, 10 (2012).
6. Tontonoz, P. & Spiegelman, B. M. Fat and beyond: the diverse biology of PPARgamma. Annu Rev Biochem 77, 289-312 (2008).
7. Kahn, B. B. & McGraw, T. E. Rosiglitazone, PPARγ, and Type 2 Diabetes. N Engl J Med 363, 2667-2669 (2010).
8. Wang, Y. X. PPARs: diverse regulators in energy metabolism and metabolic diseases. Cell Res 20, 124-137 (2010).
9. Malapaka, R. R. V. et al. Identification and Mechanism of 10-Carbon Fatty Acid as Modulating Ligand of Peroxisome Proliferatoractivated Receptors. J Biol Chem 287, 183-195 (2012).
10. Albert, B. B. et al. Higher omega-3 index is associated with increased insulin sensitivity and more favourable metabolic profile in middle-aged overweight men. Sci Rep 4, 7 (2014).
11. Gervois, P., Fruchart, J. C. & Staels, B. Drug Insight: mechanisms of action and therapeutic applications for agonists of peroxisome proliferator-activated receptors. Nat Clin Pract Endoc 3, 145-156 (2007).
12. Bruning, J. B. et al. Partial agonists activate PPARgamma using a helix 12 independent mechanism. Structure 15, 1258-1271 (2007).
13. Kallenberger, B. C., Love, J. D., Chatterjee, V. K. & Schwabe, J. W. A dynamic mechanism of nuclear receptor activation and its perturbation in a human disease. Nat Struct Biol 10, 136-140 (2003).
14. Nesto, R. W. et al. Thiazolidinedione use, fluid retention, and congestive heart failure. Diabetes Care 27, 256-263 (2004).
15. Higgins, L. S. & Depaoli, A. M. Selective peroxisome proliferator-activated receptor gamma (PPARgamma) modulation as a strategy for safer therapeutic PPARgamma activation. Am J Clin Nutr 91, 267S-272S (2010).
16. Berger, J. P. et al. Distinct properties and advantages of a novel peroxisome proliferator-activated protein gamma selective modulator. Mol Endocrinol 17, 662-676 (2003).
17. Choi, J. H. et al. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5. Nature 466, 451-456 (2010).
18. Choi, J. H. et al. Antidiabetic actions of a non-agonist PPARγ ligand blocking Cdk5-mediated phosphorylation. Nature 477 (2011).
19. Hughes, T. S. et al. Ligand and receptor dynamics contribute to the mechanism of graded PPARγ agonism. Structure 20, 139-150 (2012).
20. Nettles, K. W. & Greene, G. L. Ligand control of coregulator recruitment to nuclear receptors. Annu Rev Physiol 67, 309-333 (2005).
21. Dhavan, R. & Tsai, L. H. A decade of CDK5. Nat Rev Mol Cell Biol 2, 749-759 (2001).
22. Choi, S. S. et al. A novel non-agonist peroxisome proliferator-activated receptor γ (PPARγ) ligand UHC1 blocks PPARγ phosphorylation by cyclin-dependent kinase 5 (CDK5) and improves insulin sensitivity. J Biol Chem 289, 26618-26629 (2014).
23. Colombo, M. L. & Bosisio, E. Pharmacological activities of Chelidonium majus L.(Papaveraceae). Pharmacol Res 33, 127-134 (1996).
24. Lenfeld, J. et al. Antiinflammatory activity of quaternary benzophenanthridine alkaloids from Chelidonium majus. Planta Med. 43, 161-165 (1981).
25. Herbert, J. M., Augereau, J. M., Gleye, J. & Maffrand, J. P. Chelerythrine is a potent and specific inhibitor of protein kinase C. Biochem Biophys Res Commun 172, 993-999 (1990).
26. Li, Y. et al. Crystallographic identification and functional characterization of phospholipids as ligands for the orphan nuclear receptor steroidogenic factor-1. Mol cell 17, 491-502 (2005).
27. Perissi, V., Aggarwal, A., Glass, C. K., Rose, D. W., Rosenfeld, M. G. A corepressor/coactivator exchange complex required for transcriptional activation by nuclear receptors and other regulated transcription factors. Cell 116, 6 (2004).
28. Xu, H. E. & Li, Y. Ligand-dependent and-independent regulation of PPAR gamma and orphan nuclear receptors. Sci Signal 1, pe52 (2008).
29. Rastinejad, F., Huang, P., Chandra, V. & Khorasanizadeh, S. Understanding nuclear receptor form and function using structural biology. J Mol Endocrinol 51, T1-T21 (2013).
30. Nolte, R. T. et al. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature 395, 137-143 (1998).
31. Picard, F. & Auwerx, J. PPAR(gamma) and glucose homeostasis. Annu Rev Nutr 22, 167-197 (2002).
32. Saltiel, A. R. & Kahn, C. R. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414, 799-806 (2001).
33. Trujillo, M. E. & Scherer, P. E. Adipose tissue-derived factors: Impact on health and disease. Endocr Rev 27, 762-778 (2006).
34. Maeda, N. et al. PPAR gamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes 50, 2094-2099 (2001).
35. Banks, A. S. et al. An ERK/Cdk5 axis controls the diabetogenic actions of PPARγ Nature 517, 391-395 (2015).
36. Winn, M. D. et al. Overview of the CCP4 suite and current developments. Acta Crystallogr D Biol Crystallogr 67, 235-242 (2011).
37. Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr D Biol Crystallogr 66, 486-501 (2010).