Effect of Geldanamycin Binding on the Thr90 Phosphorylation Site of Hsp90

Main Article Content

K.A. Shcherbakov
D.S. Shcherbinin
A.V. Veselovsky

Abstract

Prostate cancer is hormone-dependent and the androgen receptor (AR) is involved in its development. AR is a transcription factor that is activated by ligand binding, result in its translocation into the nucleus, where it initiates gene transcription. In an inactive state in cytoplasm AR exists as a complex with heat shock protein 90 (HSP90) and some other proteins. When the agonist binds, a conformational change in AR occurs, resulting in HSP90 and other chaperones dissociating. Recently it has been shown that for the dissociation of the HSP90-AR complex and the translocation of the latter into the nucleus, phosphorylation of the Thr-90 residue of the N-terminal domain of HSP90 is necessary. In this work, the effect of the HSP90 inhibitor, geldanamycin, interacting with the ATP-binding site, on the Thr90 phosphorylation site was investigated by molecular modeling methods. It has been shown that inhibitor binding slightly affects the size and mobility of cavity around Thr90. It is suggested that inhibitor binding to HSP90 does not result in changing the protein structure and does not influence on protein phosphorylation, and partially explains low effectiveness of such type of drugs in the therapy of prostate cancer.

Article Details

How to Cite
Shcherbakov, K., Shcherbinin, D., & Veselovsky, A. (2021). Effect of Geldanamycin Binding on the Thr90 Phosphorylation Site of Hsp90. Biomedical Chemistry: Research and Methods, 4(3), e00145. https://doi.org/10.18097/BMCRM00145
Section
EXPERIMENTAL RESEARCH

References

  1. Culig, Z., Santer, F.R. (2014) Androgen receptor signaling in prostate cancer. Cancer Metastasis Rev., 33(2-3), 413-427. DOI
  2. Gelman, I.H. (2014) Androgen receptor activation in castration-recurrent prostate cancer: the role of Src-family and Ack1 tyrosine kinases. Int. J. Biol. Sci., 10(6), 620-626. DOI
  3. Culig, Z., Klocker, H., Bartsch, G., Hobisch, A. (2001) Androgen receptor mutations in carcinoma of the prostate: significance for endocrine therapy. Am. J. Pharmacogenomics, 1(4), 241-249. DOI
  4. Thakur, A., Roy, A., Ghosh, A., Chhabra, M., Banerjee, S. (2018) Abiraterone acetate in the treatment of prostate cancer. Biomed. Pharmacother., 101, 211-218. DOI
  5. Heinlein, C.A., Chang, C. (2004) Androgen receptor in prostate cancer. Endocr. Rev., 25(2), 276-308. DOI
  6. Dagar, M., Singh, J.P., Dagar, G., Tyagi, R.K., Bagchi, G. (2019) Phosphorylation of HSP90 by protein kinase A is essential for the nuclear translocation of androgen receptor. J. Biol. Chem., 294(22), 8699-8710. DOI
  7. Hoter, A., El-Sabban, M.E., Naim, H.Y. (2018) The HSP90 Family: Structure, Regulation, Function, and Implications in Health and Disease. Int. J. Mol. Sci., 19(9), 2560. DOI
  8. Solit, D.B., Scher, H.I., Rosen, N. (2003) Hsp90 as a therapeutic target in prostate cancer. Semin. Oncol., 30, 709-716. DOI
  9. Bohush, A., Bieganowski, P., Filipek, A. (2019) Hsp90 and Its Co-Chaperones in Neurodegenerative Diseases. Int. J. Mol. Sci., 20(20), 4976. DOI
  10. Wang, Y., McAlpine, S.R. Heat-shock protein 90 inhibitors: will they ever succeed as chemotherapeutics? (2015) Future Med. Chem., 7(2), 87-90. DOI
  11. Altieri, D.C. (2010) Mitochondrial Hsp90 chaperones as novel molecular targets in prostate cancer. Future Oncol., 6(4), 487-489. DOI
  12. Wei, T., Chang, C., Xue, L., Jieling, Zh., Jie, L. (2018) CASTp 3.0: computed atlas of surface topography of proteins. Nucleic Acids Research, 46, W363–W367. DOI
  13. Abraham, M.J., van der Spoel, D., Lindahl, E., Hess, B. and the GROMACS development team, (2020) GROMACS User Manual Release 2020
  14. Humphrey, W., Dalke, A., Schulten, K. (1996) VMD: Visual molecular dynamics. J. Mol. Graph., 14(1), 33–38. DOI
  15. The PyMOL Molecular Graphics System, Version 1.2r3pre, Schrödinger, LLC. (pymol.org/2/)
  16. Piovesan, D., Minervini, G., Tosatto, S.C.E. (2016) The RING 2.0 web server for high quality residue interaction networks. Nucleic Acids Research, 44(W1), W367-74. DOI
  17. Goenawan, I.H., Kenneth B., Lynn D.J. (2016) DyNet: visualization and analysis of dynamic molecular interaction networks. Bioinformatics, 32(17):2713-5. DOI
  18. Scardoni, G., Tosadori, G., Pratap, S., Spoto, F., Laudanna, C. (2015) Finding the shortest path with PesCa: a tool for network reconstruction. F1000Res., 4, 484. DOI
  19. Le Guilloux, V., Schmidtke, P., Tuffery, P. (2009) Fpocket: An open source platform for ligand pocket detection. BMC Bioinformatics, 10, 168. DOI
  20. Stebbins, C.E., Russo, A.A., Schneider, C., Rosen, N., Hartl, F.U., Pavletich, N.P. (1997) Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent. Cell, 89(2), 239-250. DOI