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.

  • Letter
  • Published:

Structure and autoregulation of the insulin-like growth factor 1 receptor kinase

Nature Structural Biology volume 8, pages 1058–1063 (2001)Cite this article

Abstract

The insulin-like growth factor 1 (IGF1) receptor is closely related to the insulin receptor. However, the unique biological functions of IGF1 receptor make it a target for therapeutic intervention in human cancer. Using its isolated tyrosine kinase domain, we show that the IGF1 receptor is regulated by intermolecular autophosphorylation at three sites within the kinase activation loop. Steady-state kinetic analyses of the isolated phosphorylated forms of the IGF1 receptor kinase (IGF1RK) reveal that each autophosphorylation event increases enzyme turnover number and decreases Km for ATP and peptide. We have determined the 2.1 Å-resolution crystal structure of the tris-phosphorylated form of IGF1RK in complex with an ATP analog and a specific peptide substrate. The structure of IGF1RK reveals how the enzyme recognizes peptides containing hydrophobic residues at the P+1 and P+3 positions and how autophosphorylation stabilizes the activation loop in a conformation that facilitates catalysis. Although the nucleotide binding cleft is conserved between IGF1RK and the insulin receptor kinase, sequence differences in the nearby interlobe linker could potentially be exploited for anticancer drug design.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Autophosphorylation of IGF1RK.
Figure 2: Overall structure of IGF1RK and activation loop interactions.
Figure 3: IGF1RK peptide substrate binding and comparison to IRK.

Similar content being viewed by others

Accession codes

Accessions

Protein Data Bank

References

  1. Adams, T.E., Epa, V.C., Garrett, T.P.J. & Ward, C.W. Cell. Mol. Life Sci. 57, 1050–1093 (2000).

    Article  CAS  Google Scholar 

  2. Lui, J.P., Baker, J., Perkins, A.S., Robertson, E.J. & Efstratiadis, A. Cell 75, 59–72 (1993).

    Google Scholar 

  3. Baserga, R., Hongo, A., Rubini, M., Prisco, M. & Valentinis, B. Biochim. Biophys. Acta. 1332, 105–126 (1997).

    Google Scholar 

  4. Yarden, Y. & Ullrich, A. Biochemistry 27, 3113–3119 (1988).

    Article  CAS  Google Scholar 

  5. Hubbard, S.R. & Till, J.H. Annu. Rev. Biochem. 69, 373–398 (2000).

    Article  CAS  Google Scholar 

  6. Blakesley, V.A., Scrimgeour, A., Esposito, D. & LeRoith, D. Cytokine Growth Factor Rev. 7, 153–159 (1996).

    Article  CAS  Google Scholar 

  7. Ullrich, A. et al. EMBO J. 5, 2503–2512 (1986).

    Article  CAS  Google Scholar 

  8. Lamothe, B. et al. Biochem. J. 335, 193–204 (1998).

    Article  CAS  Google Scholar 

  9. Urso, B. et al. J. Biol. Chem. 274, 30864–30873 (1999).

    Article  CAS  Google Scholar 

  10. Patti M.E. & Kahn C.R. J. Basic Clin. Physiol. Pharmacol. 9, 89–109 (1998).

    Article  CAS  Google Scholar 

  11. Lammers, R., Gray, A., Schlessinger, J. & Ullrich, A. EMBO J. 8, 1369–1375 (1989).

    Article  CAS  Google Scholar 

  12. Kato, H., Faria, T.N., Stannard, B., Roberts, C.T. Jr., & LeRoith, D. J. Biol. Chem. 268, 2655–2661 (1993).

    CAS  PubMed  Google Scholar 

  13. Murakami, M.S. & Rosen, O.M. J. Biol. Chem. 266, 22653–22660 (1991).

    CAS  PubMed  Google Scholar 

  14. Wei, L., Hubbard, S.R., Hendrickson, W.A. & Ellis, L. J. Biol. Chem. 270, 8122–8130 (1995).

    Article  CAS  Google Scholar 

  15. Butler, A.A. et al. Comp. Biochem. Physiol. 121, 19–26 (1998).

    Article  CAS  Google Scholar 

  16. Hubbard, S.R., Wei, L., Ellis, L. & Hendrickson, W.A. Nature 372, 746–754 (1994).

    Article  CAS  Google Scholar 

  17. Hubbard, S.R. EMBO J. 16, 5572–5581 (1997).

    Article  CAS  Google Scholar 

  18. Gruppuso, P.A., Boylan, J.M., Levine, B.A. & Ellis, L. Biochem. Biophys. Res. Comm. 189, 1457–1463 (1992).

    Article  CAS  Google Scholar 

  19. Al-Hasani, H., Passlack, W. & Klein, H.W. FEBS Lett. 349, 17–22 (1994).

    Article  CAS  Google Scholar 

  20. Barker, S.C. et al. Biochemistry 34, 14843–14851 (1995).

    Article  CAS  Google Scholar 

  21. Porter, M., Schindler, T., Kuriyan, J. & Miller, W.T. J. Biol. Chem. 275, 2721–2726 (2000).

    Article  CAS  Google Scholar 

  22. Moarefi, I. et al. Nature 385, 650–653 (1997).

    Article  CAS  Google Scholar 

  23. Songyang, Z. et al. Nature 373, 536–539 (1995).

    Article  CAS  Google Scholar 

  24. Ablooglu, A.J. & Kohanski, R.A. Biochemistry 40, 504–513 (2001).

    Article  CAS  Google Scholar 

  25. Xu, B., Bird, V.G. & Miller, W.T. J. Biol. Chem. 270, 29825–29830 (1995).

    Article  CAS  Google Scholar 

  26. Mohammadi, M. et al. Science 276, 955–960 (1997).

    Article  CAS  Google Scholar 

  27. Mohammadi, M. et al. EMBO J. 17, 5896–5904 (1998).

    Article  CAS  Google Scholar 

  28. Schindler, T. et al. Science 289, 1938–1942 (2000).

    Article  CAS  Google Scholar 

  29. Zhu, X. et al. Structure Fold. Des. 7, 651–661 (1999).

    Article  CAS  Google Scholar 

  30. Blum, G., Gazit, A. & Levitzki, A. Biochemistry 39, 15705–15712 (2000).

    Article  CAS  Google Scholar 

  31. Parang K. et al. Nature Struct. Biol. 8, 37–41 (2001).

    Article  CAS  Google Scholar 

  32. Otwinowski, Z. in Proceedings of the CCP4 study weekend (eds. Sawyer, L., Isaacs, N. & Baily, S.) 6–62 (SERC Daresbury Laboratory, Daresbury, UK; 1993).

    Google Scholar 

  33. Navaza, J. Acta Crystallogr. A 50, 157–163 (1994).

    Article  Google Scholar 

  34. Peitsch, M.C. Biochem. Soc. Trans. 24, 274–279 (1996).

    Article  CAS  Google Scholar 

  35. Brünger, A.T. et al. Acta Crystallogr. D 54, 905–921 (1998).

    Article  Google Scholar 

  36. Jones, T.A., Zou, J.Y., Cowan, S.W. & Kjeldgaard, M. Acta Crystallogr. A 47, 110–119 (1991).

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the NIH to S.R.H. and to W.T.M. Beamline X4A at the National Synchrotron Light Source, a DOE facility, is supported by the Howard Hughes Medical Institute.

Author information

Author notes

  1. Svetlana Favelyukis, Jeffrey H. Till and Stevan R. Hubbard: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Physiology and Biophysics, School of Medicine State University of New York at Stony Brook, Stony Brook, 11794, New York, USA

    Svetlana Favelyukis & W. Todd Miller

  2. Skirball Institute of Biomolecular Medicine and Department of Pharmacology, New York University School of Medicine, New York, 10016, New York, USA

    Jeffrey H. Till & Stevan R. Hubbard

Authors
  1. Svetlana Favelyukis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeffrey H. Till
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stevan R. Hubbard
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. W. Todd Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Stevan R. Hubbard or W. Todd Miller.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Favelyukis, S., Till, J., Hubbard, S. et al. Structure and autoregulation of the insulin-like growth factor 1 receptor kinase. Nat Struct Mol Biol 8, 1058–1063 (2001). https://doi.org/10.1038/nsb721

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsb721

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing