Advertisement

Journal of Computer-Aided Molecular Design

, Volume 21, Issue 10–11, pp 641–648 | Cite as

Computational study on mechanism of G-quartet oligonucleotide T40214 selectively targeting Stat3

  • Qiqing Zhu
  • Naijie Jing
Article

Abstract

The mounting evidences have shown that signal transducer and activator of transcription 3 (Stat3) is a critical target for cancer therapy. Recently, we developed a G-quartet oligonucleotide T40214 as a novel and potent Stat3 inhibitor. T40214 specifically inhibited DNA-binding activity of Stat3 and significantly suppressed the growth of many tumor xenografts in nude mice. To determine the mechanism of GQ-ODNs selectively targeting Stat3, we established a 3D model of complex T40214/p-Stat3 dimer based on experimental evidences. The binding site of T40214 within Stat3 dimer was determined by statistical docking analysis. The results indicated that T40214 strongly interacted within the region from residue E638 through E652 of Stat3 dimer. The binding model refined by Hex docking disclosed that T40214 binds to SH2 domain of Stat3 and forms H-bonds with residues Q643, Q644, N646, and N647, which are critical for the binding interaction. The 3D models also suggested that T40214 inhibits Stat3 activity through disrupting the binding interaction between Stat3 dimer and DNA duplex for transcription. Our computational studies provided a platform for future structure-based drug design of novel Stat3 inhibitors.

Keywords

Stat3 Stat1 Molecular docking T40214 GQ-ODN 

Notes

Acknowledgments

The authors wish to thank Yidong Li, who contributed to this study by providing the EMSA results. This project was supported by the following grants: CA104035 (NIH) and competitive award from Prostate Cancer Foundation. In addition, Dr. Zhu received support through NIH training grant T32 DK60445.

References

  1. 1.
    Darnell JE (1997) Science 277:1630CrossRefGoogle Scholar
  2. 2.
    Bromberg J, Darnell JE (2000) Oncogene 19:2468CrossRefGoogle Scholar
  3. 3.
    Darnell JE (2002) Nat Rev Cancer 2:740CrossRefGoogle Scholar
  4. 4.
    Heinrich PC, Behrmann I, Muller-Newen G, Schaper F, Graeve L (1998) Biochem J 334(Pt 2):297Google Scholar
  5. 5.
    Hirano T, Ishihara K, Hibi M (2000) Oncogene 19:2548CrossRefGoogle Scholar
  6. 6.
    Takeda K, Akira S (2000) Cytokine Growth Factor Rev 11:199CrossRefGoogle Scholar
  7. 7.
    Lutticken C, Wegenka UM, Yuan J, Buschmann J, Schindler C, Ziemiecki A, Harpur AG, Wilks AF, Yasukawa K, Taga T et al (1994) Science 263:89CrossRefGoogle Scholar
  8. 8.
    Raz R, Durbin JE, Levy DE (1994) J Biol Chem 269:24391Google Scholar
  9. 9.
    Wegenka UM, Lutticken C, Buschmann J, Yuan J, Lottspeich F, Muller-Esterl W, Schindler C, Roeb E, Heinrich PC, Horn F (1994) Mol Cell Biol 14:3186Google Scholar
  10. 10.
    Zhong Z, Wen Z, Darnell JE Jr (1994) Science 264:95CrossRefGoogle Scholar
  11. 11.
    Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R, Ciliberto G, Moscinski L, Fernandez-Luna JL, Nunez G, Dalton WS, Jove R (1999) Immunity 10:105CrossRefGoogle Scholar
  12. 12.
    Grandis JR, Drenning SD, Chakraborty A, Zhou MY, Zeng Q, Pitt AS, Tweardy DJ (1998) J Clin Invest 102:1385Google Scholar
  13. 13.
    Bowman T, Garcia R, Turkson J, Jove R (2000) Oncogene 19:2474CrossRefGoogle Scholar
  14. 14.
    Buettner R, Mora LB, Jove R (2002) Clin Cancer Res 8:945Google Scholar
  15. 15.
    Silvennoinen O, Schindler C, Schlessinger J, Levy DE (1993) Science 261:1736CrossRefGoogle Scholar
  16. 16.
    Darnell JE Jr, Kerr IM, Stark GR (1994) Science 264:1415CrossRefGoogle Scholar
  17. 17.
    Levy DE, Darnell JE Jr (2002) Nat Rev Mol Cell Biol 3:651CrossRefGoogle Scholar
  18. 18.
    Becker S, Groner B, Muller CW (1998) Nature 394:145CrossRefGoogle Scholar
  19. 19.
    Chen X, Vinkemeier U, Zhao Y, Jeruzalmi D, Darnell JE Jr, Kuriyan J (1998) Cell 93:827CrossRefGoogle Scholar
  20. 20.
    Xu X, Sun YL, Hoey T (1996) Science 273:794CrossRefGoogle Scholar
  21. 21.
    Horvath CM, Wen Z, Darnell JE Jr (1995) Genes Dev 9:984CrossRefGoogle Scholar
  22. 22.
    Shuai K, Horvath CM, Huang LH, Qureshi SA, Cowburn D, Darnell JE Jr (1994) Cell 76:821CrossRefGoogle Scholar
  23. 23.
    Jing N, Tweardy DJ (2005) Anticancer Drugs 16:601CrossRefGoogle Scholar
  24. 24.
    Jing N, Li Y, Xu X, Sha W, Li P, Feng L, Tweardy DJ (2003) DNA Cell Biol 22:685CrossRefGoogle Scholar
  25. 25.
    Weerasinghe P, Garcia GE, Zhu Q, Yuan P, Feng L, Mao L, Jing N (2007) Int J Oncol 31:129Google Scholar
  26. 26.
    Jing N, Zhu Q, Yuan P, Li Y, Mao L, Tweardy DJ (2006) Mol Cancer Ther 5:279CrossRefGoogle Scholar
  27. 27.
    Jing N, Li Y, Xiong W, Sha W, Jing L, Tweardy DJ (2004) Cancer Res 64:6603CrossRefGoogle Scholar
  28. 28.
    Grandis JR, Drenning SD, Zeng Q, Watkins SC, Melhem MF, Endo S, Johnson DE, Huang L, He Y, Kim JD (2000) Proc Natl Acad Sci USA 97:4227CrossRefGoogle Scholar
  29. 29.
    Ramana CV, Grammatikakis N, Chernov M, Nguyen H, Goh KC, Williams BR, Stark GR (2000) Embo J 19:263CrossRefGoogle Scholar
  30. 30.
    Yu H, Jove R (2004) Nat Rev Cancer 4:97CrossRefGoogle Scholar
  31. 31.
    Jing N, Hogan ME (1998) J Biol Chem 273:34992CrossRefGoogle Scholar
  32. 32.
    Pearlmann DA, Case DA, Caldwell JW, Ross WS, Cheatham TE, III DeBolt S, Ferguson D, Seibel G, Kollman P (1995) Comp Phys Commun 91:1CrossRefGoogle Scholar
  33. 33.
    Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) Nucleic Acids Res 28:235CrossRefGoogle Scholar
  34. 34.
    Berman HM, Olson WK, Beveridge DL, Westbrook J, Gelbin A, Demeny T, Hsieh SH, Srinivasan AR, Schneider B (1992) Biophys J 63:751Google Scholar
  35. 35.
    Ritchie DW, Kemp GJ (2000) Proteins 39:178CrossRefGoogle Scholar
  36. 36.
    Boeckmann B, Bairoch A, Apweiler R, Blatter MC, Estreicher A, Gasteiger E, Martin MJ, Michoud K, O’Donovan C, Phan I, Pilbout S, Schneider M (2003) Nucleic Acids Res 31:365CrossRefGoogle Scholar
  37. 37.
    Thompson JD, Higgins DG, Gibson TJ (1994) Nucleic Acids Res 22:4673CrossRefGoogle Scholar
  38. 38.
    Neculai D, Neculai AM, Verrier S, Straub K, Klumpp K, Pfitzner E, Becker S (2005) J Biol Chem 280:40782CrossRefGoogle Scholar
  39. 39.
    Mao X, Ren Z, Parker GN, Sondermann H, Pastorello MA, Wang W, McMurray JS, Demeler B, Darnell JE Jr, Chen X (2005) Mol Cell 17:761CrossRefGoogle Scholar
  40. 40.
    Soler-Lopez M, Petosa C, Fukuzawa M, Ravelli R, Williams JG, Muller CW (2004) Mol Cell 13:791CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2007

Authors and Affiliations

  1. 1.Department of MedicineBaylor College of MedicineHoustonUSA
  2. 2.Cancer CenterBaylor College of MedicineHoustonUSA

Personalised recommendations