Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

An orthosteric inhibitor of the Ras-Sos interaction

Nature Chemical Biology volume 7, pages 585–587 (2011)Cite this article

Subjects

This article has been updated

Abstract

Mimics of α-helices on protein surfaces have emerged as powerful reagents for antagonizing protein-protein interactions, which are difficult to target with small molecules. Here we describe the design of a cell-permeable synthetic α-helix, based on the guanine nucleotide exchange factor Sos, that interferes with Ras-Sos interaction and downregulates Ras signaling in response to receptor tyrosine kinase activation.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The Ras-Sos interface and rational design of synthetic inhibitors.
Figure 2: HBS 3 inhibits the Ras-ERK pathway.

Similar content being viewed by others

Change history

  • 04 August 2011

    In the version of this article initially published online, the description of the control analog HBS 7 incorrectly stated that "three alanines were replaced with residues that are important for interaction: Phe929, Glu942 and Asn944." It should have said that in this analog "the residues that are important for interaction, Phe929, Glu942 and Asn944, were replaced with alanine residues." The error has been corrected for the print, PDF and HTML versions of this article.

References

  1. Blume-Jensen, P. & Hunter, T. Nature 411, 355–365 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Buday, L. & Downward, J. Biochim. Biophys. Acta 1786, 178–187 (2008).

    CAS  PubMed  Google Scholar 

  3. Konstantinopoulos, P.A., Karamouzis, M.V. & Papavassiliou, A.G. Nat. Rev. Drug Discov. 6, 541–555 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Kortemme, T., Kim, D.E. & Baker, D. Sci. STKE 2004, pl2 (2004).

    PubMed  Google Scholar 

  5. Hall, B.E., Yang, S.S., Boriack-Sjodin, P.A., Kuriyan, J. & Bar-Sagi, D. J. Biol. Chem. 276, 27629–27637 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Patgiri, A., Jochim, A.L. & Arora, P.S. Acc. Chem. Res. 41, 1289–1300 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Henchey, L.K., Porter, J.R., Ghosh, I. & Arora, P.S. ChemBioChem 11, 2104–2107 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Henchey, L.K. et al. J. Am. Chem. Soc. 132, 941–943 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sondermann, H. et al. Cell 119, 393–405 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Chakrabartty, A., Kortemme, T. & Baldwin, R.L. Protein Sci. 3, 843–852 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Patgiri, A., Menzenski, M.Z., Mahon, A.B. & Arora, P.S. Nat. Protoc. 5, 1857–1865 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Boriack-Sjodin, P.A., Margarit, S.M., Bar-Sagi, D. & Kuriyan, J. Nature 394, 337–343 (1998).

    Article  CAS  PubMed  Google Scholar 

  13. Sacco, E. et al. FEBS Lett. 579, 6851–6858 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Ito, Y. et al. Biochemistry 36, 9109–9119 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Moellering, R.E. et al. Nature 462, 182–188 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Boykevisch, S. et al. Curr. Biol. 16, 2173–2179 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Gureasko, J. et al. Nat. Struct. Mol. Biol. 15, 452–461 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kolch, W. Nat. Rev. Mol. Cell Biol. 6, 827–837 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Kholodenko, B.N., Hancock, J.F. & Kolch, W. Nat. Rev. Mol. Cell Biol. 11, 414–426 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Harrison, R.S. et al. Proc. Natl. Acad. Sci. USA 107, 11686–11691 (2010).

    Article  CAS  PubMed  Google Scholar 

  21. Horne, W.S. et al. Proc. Natl. Acad. Sci. USA 106, 14751–14756 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Cummings, C.G. & Hamilton, A.D. Curr. Opin. Chem. Biol. 14, 341–346 (2010).

    Article  CAS  PubMed  Google Scholar 

  23. McKay, M.M. & Morrison, D.K. Oncogene 26, 3113–3121 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Lemmon, M.A. & Schlessinger, J. Cell 141, 1117–1134 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the US National Institutes of Health (GM073943 to P.S.A. and GM078266 and an ARRA stimulus supplement (GM078266S1) to D.B.-S.). A.P. thanks New York University for the Margaret and Herman Sokol Fellowship. NMR data were collected at the New York Structural Biology Center, a Strategically Targeted Academic Research (STAR) center supported by the New York State Office of Science, Technology and Academic Research. We thank C. Lin (New York University) and A. Natarajan and R. Ghosh (City College, City University of New York) for help with the NMR studies.

Author information

Author notes

  1. Anupam Patgiri and Kamlesh K Yadav: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Chemistry, New York University, New York, New York, USA

    Anupam Patgiri & Paramjit S Arora

  2. Department of Biochemistry, New York University School of Medicine, New York, New York, USA

    Kamlesh K Yadav & Dafna Bar-Sagi

Authors
  1. Anupam Patgiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kamlesh K Yadav
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paramjit S Arora
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dafna Bar-Sagi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.P., K.K.Y., P.S.A. and D.B.-S. designed experiments, analyzed data and wrote the paper, and A.P. and K.K.Y. performed experiments.

Corresponding authors

Correspondence to Paramjit S Arora or Dafna Bar-Sagi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Methods and Supplementary Results (PDF 8228 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Patgiri, A., Yadav, K., Arora, P. et al. An orthosteric inhibitor of the Ras-Sos interaction. Nat Chem Biol 7, 585–587 (2011). https://doi.org/10.1038/nchembio.612

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchembio.612

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research