Skip to main content
SpringerLink
Log in

Complex structure of human Hsp90N and a novel small inhibitor FS5

  • Published:
Nuclear Science and Techniques Aims and scope Submit manuscript

Abstract

Heat shock proteins (Hsps) are a family of abundantly expressed ATP-dependent chaperone proteins. Hsp90 is an eminent member of Hsp family. Thus far, two primary functions have been described for Hsp90: first, as a regulator of conformational change of some protein kinases and nuclear hormone receptors, and the other as an indispensable factor in cellular stress response. Hsp90 has an essential number of interaction proteins since it participates in almost every biological process and its importance is self-evident. Hsp90 has an inextricable relationship in the pathogenesis of cancer, especially in the proliferation and irradiation of cancer cells, thus being a notable cancer target. Since the discovery of geldanamycin, the first inhibitor of Hsp90, from the bacterial species Streptomyces hygroscopicus, even more attention has been focused toward Hsp90. Many structure-based inhibitors of Hsp90 have been designed to develop an innovative method to defeat cancer. However, already designed inhibitors have various deficiencies, such as hepatotoxicity, poor aqueous solubility, instability, and non-ideal oral bioavailability. Based on the aforementioned reasons and to achieve an optimal performance and fewer side effects, we designed a novel inhibitor of Hsp90, called FS5, and resolved the crystal structure of the Hsp90N-FS5 complex (1.65 Å, PDB code 5XRB). Furthermore, we compared the complexes Hsp90N, Hsp90N-GDM, and Hsp90N-ATP and suggest that the inhibitor FS5 may compete with ATP for binding to Hsp90, which can be regarded as a potential strategy for the development of novel cancer drugs in the future.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. W.J. Welch, Mammalian stress response: cell physiology, structure/function of stress proteins, and implications for medicine and disease. Physiol. Rev. 72, 1063–1081 (1992). https://doi.org/10.1152/physrev.1992.72.4.1063

    Article  Google Scholar 

  2. M. Brehme, C. Voisine, Model systems of protein-misfolding diseases reveal chaperone modifiers of proteotoxicity. Dis. Model. Mech. 9, 823–838 (2016). https://doi.org/10.1242/dmm.024703

    Article  Google Scholar 

  3. M. Brehme, C. Voisine, T. Rolland et al., A chaperome subnetwork safeguards proteostasis in aging and neurodegenerative disease. Cell. Rep. 9, 1135–1150 (2014). https://doi.org/10.1016/j.celrep.2014.09.042

    Article  Google Scholar 

  4. W.J. Welch, J.R. Feramisco, Purification of the major mammalian heat shock proteins. J. Biol. Chem. 257, 14949–14959 (1982). https://doi.org/10.1086/283964

    Article  Google Scholar 

  5. C.E. Stebbins, A.A. Russo, C. Schneider et al., Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent. Cell 89, 239–250 (1997). https://doi.org/10.1016/s0092-8674(00)80203-2

    Article  Google Scholar 

  6. F. Jiang, H.J. Wang, Y.H. Jin et al., Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90. J. Med. Chem. 59, 10498–10519 (2016). https://doi.org/10.1021/acs.jmedchem.6b00912

    Article  Google Scholar 

  7. W.B. Prat, D.O. Toft, Steroid receptor interactions with heat shock protein and immunophilin chaperones. Endocr. Rev. 18, 306–360 (1997). https://doi.org/10.1210/edrv.18.3.0303

    Article  Google Scholar 

  8. A.J. McClellan, Y. Xia, A.M. Deutschbauer et al., Diverse cellular functions of the Hsp90 molecular chaperone uncovered using systems approaches. Cell. 131, 121–135 (2007). https://doi.org/10.1016/j.cell.2007.07.036

    Article  Google Scholar 

  9. D.C. Dezwaan, B.C. Freeman, HSP90: the Rosetta stone for cellular protein dynamics? Cell Cycle 7, 1006–1012 (2008). https://doi.org/10.4161/cc.7.8.5723

    Article  Google Scholar 

  10. M. Taipale, D.F. Jarosz, S. Lindquist, HSP90 at the hub of protein homeostasis: emerging mechanistic insights. Nat. Rev. Mol. Cell Biol. 11, 515–528 (2010). https://doi.org/10.1038/nrm2918

    Article  Google Scholar 

  11. L. Wang, L. Li, Z.H. Zhou et al., Structure-based virtual screening and optimization of modulators targeting Hsp90-Cdc37 interaction. Eur. J. Med. Chem. 136, 63–73 (2017). https://doi.org/10.1016/j.ejmech.2017.04.074

    Article  Google Scholar 

  12. K. Jhaveri, S.O. Ochiana, M.P. Dunphy et al., Heat shock protein 90 inhibitors in the treatment of cancer: current status and future directions. Expert. Opin. Investig. Drugs. 23, 611–628 (2014). https://doi.org/10.1517/13543784.2014.902442

    Article  Google Scholar 

  13. X. Chen, P. Liu, Q. Wang et al., DCZ3112, a novel Hsp90 inhibitor, exerts potent antitumor activity against HER2-positive breast cancer through disruption of Hsp90-Cdc37 interaction. Cancer. Lett. 434, 70–80 (2018). https://doi.org/10.1016/j.canlet.2018.07.012

    Article  Google Scholar 

  14. N. Li, M. Xu, B. Wang et al., Discovery of Novel Celastrol Derivatives as Hsp90-Cdc37 Interaction Disruptors with Antitumor Activity. J. Med. Chem. 62, 10798–10815 (2019). https://doi.org/10.1021/acs.jmedchem.9b01290

    Article  Google Scholar 

  15. W. Chen, R. Zheng, P.D. Baade et al., Cancer statistics in China. CA. Cancer. J. Clin. 66, 115–132 (2015). https://doi.org/10.3322/caac.21338

    Article  Google Scholar 

  16. J.R. Porter, C.C. Fritz, K.M. Depew, Discovery and development of Hsp90 inhibitors: a promising pathway for cancer therapy. Curr. Opin. Chem. Biol. 14, 412–420 (2010). https://doi.org/10.1016/j.cbpa.2010.03.019

    Article  Google Scholar 

  17. G. Chiosis, L. Neckers, Tumor selectivity of Hsp90 inhibitors: the explanation remains elusive. ACS Chem. Biol. 1, 279–284 (2006). https://doi.org/10.1021/cb600224w

    Article  Google Scholar 

  18. F.H. Schopf, M.M. Biebl, J. Buchner, The HSP90 chaperone machinery. Nat. Rev. Mol. Cell Biol. 18, 345–360 (2017). https://doi.org/10.1038/nrm.2017.20

    Article  Google Scholar 

  19. H.J. Patel, S. Modi, G. Chiosis et al., Advances in the discovery and development of heat-shock protein 90 inhibitors for cancer treatment. Expert. Opin. Drug. Discov. 6, 559–587 (2011). https://doi.org/10.1517/17460441.2011.563296

    Article  Google Scholar 

  20. A. Maloney, P. Workman, HSP90 as a new therapeutic target for cancer therapy: the story unfolds. Expert Opin Biol Ther 2002(2), 3–24 (2002). https://doi.org/10.1517/14712598.2.1.3

    Article  Google Scholar 

  21. N. Wayne, D.N. Bolon, Dimerization of Hsp90 is required for in vivo function. Design and analysis of monomers and dimers. J. Biol. Chem. 282, 35386–35395 (2007). https://doi.org/10.1074/jbc.M703844200

    Article  Google Scholar 

  22. C. Prodromou, S.M. Roe, R. O'Brien et al., Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone. Cell 90, 65–75 (1997). https://doi.org/10.1016/s0092-8674(00)80314-1

    Article  Google Scholar 

  23. K. Terasawa, M. Minami, Y. Minami, Constantly updated knowledge of Hsp90. J. Biochem. 137, 443–447 (2005). https://doi.org/10.1093/jb/mvi056

    Article  Google Scholar 

  24. K.A. Verba, R.Y. Wang, A. Arakawa et al., Atomic structure of Hsp90-Cdc37-Cdk4 reveals that Hsp90 traps and stabilizes an unfolded kinase. Science. 352, 1542–1547. https://doi.org/10.1126/science.aaf5023

    Article  Google Scholar 

  25. Y. Li, T. Zhang, S.J. Schwartz et al., New developments in Hsp90 inhibitors as anti-cancer therapeutics: mechanisms, clinical perspective and more potential. Drug. Resist. Updat. 12, 17–27 (2008). https://doi.org/10.1016/j.drup.2008.12.002

    Article  Google Scholar 

  26. Y. Minami, Y. Kimura, H. Kawasaki et al., The carboxy-terminal region of mammalian HSP90 is required for its dimerization and function in vivo. Mol. Cell. Biol. 14, 1459–1464 (1994). https://doi.org/10.1128/mcb.14.2.1459

    Article  Google Scholar 

  27. P. Meyer, C. Prodromou, C. Liao et al., Structural basis for recruitment of the ATPase activator Aha1 to the Hsp90 chaperone machinery. Embo j. 23, 1402–1410 (2004). https://doi.org/10.1038/sj.emboj.7600141

    Article  Google Scholar 

  28. T.O. Street, L.A. Lavery, D.A. Agard, Substrate binding drives large-scale conformational changes in the Hsp90 molecular chaperone. Mol. Cell. 42, 96–105 (2011). https://doi.org/10.1016/j.molcel.2011.01.029

    Article  Google Scholar 

  29. B. Hellenkamp, P. Wortmann, F. Kandzia et al., Multidomain structure and correlated dynamics determined by self-consistent FRET networks. Nat. Methods. 14, 174–180 (2017). https://doi.org/10.1038/nmeth.4081

    Article  Google Scholar 

  30. M. Ammirante, A. Rosati, A. Gentilella et al., The activity of Hsp90 alpha promoter is regulated by NF-kappa B transcription factors. Oncogene 27, 1175–1178 (2008). https://doi.org/10.1038/sj.onc.1210716

    Article  Google Scholar 

  31. A.K. Voss, T. Thomas, P. Gruss, Mice lacking HSP90beta fail to develop a placental labyrinth. Development. 127, 1–11 (2000). https://doi.org/10.1016/S0070-2153(00)50008-8

    Article  Google Scholar 

  32. A.K. Shiau, S. F. Harris, D. R. Southworth et al., Structural Analysis of E. coli Hsp90 reveals dramatic nucleotide-dependent conformational rearrangements. Cell. 127, 329–340 (2006). https://doi.org/10.1016/j.cell.2006.09.027

    Article  Google Scholar 

  33. D.E. Dollins, J.J. Warren, R.M. Immormino et al., Structures of GRP94-nucleotide complexes reveal mechanistic differences between the Hsp90 chaperones. Mol. Cell. 28, 41–56 (2007). https://doi.org/10.1016/j.molcel.2007.08.024

    Article  Google Scholar 

  34. R.C. Vasko, R.A. Rodriguez, C.N. Cunningham et al., Mechanistic studies of Sansalvamide A-amide: an allosteric modulator of Hsp90. ACS. Med. Chem. Lett. 1, 4–8 (2010). https://doi.org/10.1021/ml900003t

    Article  Google Scholar 

  35. S. Messaoudi, J.F. Peyrat, J.D.Brion et al., Recent advances in Hsp90 inhibitors as antitumor agents. Anticancer Agents Med Chem, 8, 761–782 (2008). https://doi.org/10.2174/187152008785914824

    Article  Google Scholar 

  36. S.J. Mishra, S. Ghosh, A.R. Stothert et al., Transformation of the Non-Selective Aminocyclohexanol-Based Hsp90 Inhibitor into a Grp94-Seletive Scaffold. ACS Chem. Biol. 12, 244–253 (2017). https://doi.org/10.1021/acschembio.6b00747

    Article  Google Scholar 

  37. L. Wang, L. Zhang, L. Li et al., Small-molecule inhibitor targeting the Hsp90-Cdc37 protein-protein interaction in colorectal cancer. Sci. Adv. 5, eaax2277(2019). https://doi.org/10.1126/sciadv.aax2277

    Article  Google Scholar 

  38. H.J. Ochel, T.W. Schulte, P. Nguyen et al., The benzoquinone ansamycin geldanamycin stimulates proteolytic degradation of focal adhesion kinase. Mol. Genet. Metab. 66, 24–30 (1999). https://doi.org/10.1006/mgme.1998.2774

    Article  Google Scholar 

  39. L. Neckers, T.W. Schulte, E. Mimnaugh, Geldanamycin as a potential anti-cancer agent: its molecular target and biochemical activity. Invest. New. Drugs. 17, 361–373 (1999). https://doi.org/10.1023/a:1006382320697

    Article  Google Scholar 

  40. L. Li, L. Wang, Q.D. You et al., Heat shock protein 90 inhibitors: an update on achievements, challenges, and future directions. J. Med. Chem., 2019. https://doi.org/10.1021/acs.jmedchem.9b00940

    Article  Google Scholar 

  41. W. Wang, Y. Liu, Z. Zhao et al., Y-632 inhibits heat shock protein 90 (Hsp90) function by disrupting the interaction between Hsp90 and Hsp70/Hsp90 organizing protein, and exerts antitumor activity in vitro and in vivo. Cancer. Sci. 107, 782–790 (2016). https://doi.org/10.1111/cas.12934

    Article  Google Scholar 

  42. D.B. Solit, F.F, Zheng, M. Drobnjak et al., 17-Allylamino-17-demethoxygeldanamycin induces the degradation of androgen receptor and HER-2/neu and inhibits the growth of prostate cancer xenografts. Clin. Cancer Res. 8, 986–993 (2002). https://doi.org/10.1159/000057670

    Article  Google Scholar 

  43. D. Chen, A. Shen, J. Li et al., Discovery of potent N-(isoxazol-5-yl)amides as HSP90 inhibitors. Eur. J. Med. Chem. 87, 765–781 (2014). https://doi.org/10.1016/j.ejmech.2014.09.065

    Article  Google Scholar 

  44. H. Cao, K. Lyu., B. Liu et al., Discovery of a novel small inhibitor RJ19 targeting to human Hsp90. Nucl. Sci. Tech. 28, 70–77 ( 2017). https://doi.org/10.1007/s41365-017-0300-1

    Article  Google Scholar 

  45. J. Li, L. Sun, C. Xu et al., Structure insights into mechanisms of ATP hydrolysis and the activation of human heat-shock protein 90. Acta. Biochim. Biophys. Sin. (Shanghai) 44, 300–306 (2012). https://doi.org/10.1093/abbs/gms001

    Article  Google Scholar 

  46. J. Bussenius, C.M. Blazey, N. Aay et al., Discovery of XL888: a novel tropane-derived small molecule inhibitor of HSP90. Bioorg. Med. Chem. Lett. 22, 5396–54049 (2012). https://doi.org/10.1016/j.bmcl.2012.07.052

    Article  Google Scholar 

  47. G. Fogliatto, L. Gianellini, M.G. Brasca et al., NMS-E973, a novel synthetic inhibitor of Hsp90 with activity against multiple models of drug resistance to targeted agents, including intracranial metastases. Clin. Cancer. Res. 19, 3520–3532 (2013). https://doi.org/10.1158/1078-0432.Ccr-12-3512

    Article  Google Scholar 

  48. J.M. Jez, J.C. Chen, G. Rastelli et al., Crystal structure and molecular modeling of 17-DMAG in complex with human Hsp90. Chem. Biol. 10, 361–368 (2003). https://doi.org/10.1016/s1074-5521(03)00075-9

    Article  Google Scholar 

  49. J. Shi, R. Van de Water, K. Hong et al., EC144 is a potent inhibitor of the heat shock protein 90. J. Med. Chem. 55, 7786–7795 (2012). https://doi.org/10.1021/jm300810x

    Article  Google Scholar 

Download references

Author information

Author notes

  1. Rui Liu, Xiao-Lu Lu, and Xian-Hua Huang have contributed equally to this work.

Authors and Affiliations

  1. School of Basic Medical Sciences, Nanchang University, Nanchang, 330031, China

    Rui Liu & Jin Zhang

  2. College of Pharmaceutical Sciences, Gannan Medical University, Ganzhou, 341000, China

    Rui Liu, Xiao-Lu Lu, Xian-Hua Huang, Wei He & Jian Li

  3. Human Aging Research Institute (HARI), School of Life Sciences, Nanchang University, Nanchang, 330031, China

    Jing-Jing Duan

  4. Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, 341000, China

    Jian Li

Authors
  1. Rui Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiao-Lu Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xian-Hua Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wei He
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jing-Jing Duan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jian Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jin Zhang or Jian Li.

Additional information

This work was supported by the Open Project of Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education (No. XN201904), Gannan Medical University (No. QD201910), the National Natural Science Foundation of China (Nos. 31770795 and 31971043), and the Jiangxi Province Natural Science Foundation (No. 20181ACB20014).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, R., Lu, XL., Huang, XH. et al. Complex structure of human Hsp90N and a novel small inhibitor FS5. NUCL SCI TECH 31, 30 (2020). https://doi.org/10.1007/s41365-020-0739-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s41365-020-0739-3

Keywords

Search

Navigation