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 of the extracellular region of HER2 alone and in complex with the Herceptin Fab

Abstract

HER2 (also known as Neu, ErbB2) is a member of the epidermal growth factor receptor (EGFR; also known as ErbB) family of receptor tyrosine kinases, which in humans includes HER1 (EGFR, ERBB1), HER2, HER3 (ERBB3) and HER4 (ERBB4)1. ErbB receptors are essential mediators of cell proliferation and differentiation in the developing embryo and in adult tissues2, and their inappropriate activation is associated with the development and severity of many cancers3. Overexpression of HER2 is found in 20–30% of human breast cancers, and correlates with more aggressive tumours and a poorer prognosis4. Anticancer therapies targeting ErbB receptors have shown promise, and a monoclonal antibody against HER2, Herceptin (also known as trastuzumab), is currently in use as a treatment for breast cancer5. Here we report crystal structures of the entire extracellular regions of rat HER2 at 2.4 Å and human HER2 complexed with the Herceptin antigen-binding fragment (Fab) at 2.5 Å. These structures reveal a fixed conformation for HER2 that resembles a ligand-activated state, and show HER2 poised to interact with other ErbB receptors in the absence of direct ligand binding. Herceptin binds to the juxtamembrane region of HER2, identifying this site as a target for anticancer therapies.

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

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

Figure 1: The structure of rat and human sHER2.
Figure 2: Superposition of different ErbB receptors.
Figure 3: Relationship of sHER2 to ligand-activated sHER1.
Figure 4: The Herceptin-binding site.

Similar content being viewed by others

References

  1. Yarden, Y. & Sliwkowski, M. X. Untangling the ErbB signalling network. Nature Rev. Mol. Cell Biol. 2, 127–137 (2001)

    Article  CAS  Google Scholar 

  2. Olayioye, M. A., Neve, R. M., Lane, H. A. & Hynes, N. E. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J. 19, 3159–3167 (2000)

    Article  CAS  Google Scholar 

  3. Tang, C. K. & Lippman, M. E. in Hormones and Signaling (ed. O'Malley, B. W.) 113–165 (Academic, San Diego, 1998)

    Book  Google Scholar 

  4. Slamon, D. J. et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235, 177–182 (1987)

    Article  ADS  CAS  Google Scholar 

  5. Slamon, D. J. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpress HER2. N. Engl. J. Med. 344, 783–792 (2001)

    Article  CAS  Google Scholar 

  6. Carpenter, G. Receptors for epidermal growth factor and other polypeptide mitogens. Annu. Rev. Biochem. 56, 881–914 (1987)

    Article  CAS  Google Scholar 

  7. Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 103, 211–225 (2000)

    Article  CAS  Google Scholar 

  8. Jones, J. T., Akita, R. W. & Sliwkowski, M. X. Binding specificities and affinities of egf domains for ErbB receptors. FEBS Lett. 447, 227–231 (1999)

    Article  CAS  Google Scholar 

  9. Di Fiore, P. P. et al. erbB-2 is a potent oncogene when overexpressed in NIH/3T3 cells. Science 237, 178–182 (1987)

    Article  ADS  CAS  Google Scholar 

  10. Ogiso, H. et al. Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains. Cell 110, 775–787 (2002)

    Article  CAS  Google Scholar 

  11. Garrett, T. P. J. et al. Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor α. Cell 110, 763–773 (2002)

    Article  CAS  Google Scholar 

  12. Ferguson, K. M. et al. EGF activates its receptor by relieving auto-inhibition of ectodomain dimerization. Mol. Cell (in the press)

  13. Cho, H. S. & Leahy, D. J. Structure of the extracellular region of HER3 reveals an interdomain tether. Science 297, 1330–1333 (2002)

    Article  ADS  CAS  Google Scholar 

  14. Banfield, M. J., King, D. J., Mountain, A. & Brady, R. L. VL:VH domain rotations in engineered antibodies: crystal structures of the Fab fragments from two murine antitumor antibodies and their engineered human constructs. Proteins 29, 161–171 (1997)

    Article  CAS  Google Scholar 

  15. Lawrence, M. C. & Colman, P. M. Shape complementarity at protein/protein interfaces. J. Mol. Biol. 234, 946–950 (1993)

    Article  CAS  Google Scholar 

  16. Berezov, A. et al. Disabling receptor ensembles with rationally designed interface peptidomimetics. J. Biol. Chem. 277, 28330–28339 (2002)

    Article  CAS  Google Scholar 

  17. Harari, D. & Yarden, Y. Molecular mechanisms underlying ErbB2/HER2 action in breast cancer. Oncogene 19, 6102–6114 (2000)

    Article  CAS  Google Scholar 

  18. Sliwkowski, M. X. et al. Nonclinical studies addressing the mechanism of action of Trastuzumab (Herceptin). Semin. Oncol. 26, 60–70 (1999)

    CAS  PubMed  Google Scholar 

  19. Molina, M. A. et al. Trastuzumab (Herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells. Cancer Res. 61, 4744–4749 (2001)

    CAS  PubMed  Google Scholar 

  20. Burke, C. L., Lemmon, M. A., Coren, B. A., Engelman, D. M. & Stern, D. F. Dimerization of the p185neu transmembrane domain is necessary but not sufficient for transformation. Oncogene 14, 687–696 (1997)

    Article  CAS  Google Scholar 

  21. Denney, D. W. Jr Gene amplification methods. US patent 5,776,746 (1998).

  22. Leahy, D. J., Dann, C. E., Longo, P., Perman, B. & Ramyar, K. X. A mammalian expression vector for expression and purification of secreted proteins for structural studies. Protein Expr. Purif. 20, 500–506 (2000)

    Article  CAS  Google Scholar 

  23. Navaza, J. AMoRe: an automated package for molecular replacement. Acta Crystallogr. A 50, 157–163 (1994)

    Article  Google Scholar 

  24. Brunger, A. T. et al. Crystallography & NMR system: a new software suite for macromolecular structure determination. Acta Crystallogr. D 54, 905–921 (1998)

    Article  CAS  Google Scholar 

  25. Vagin, A. & Teplyakov, A. MOLREP: an automated program for molecular replacement. J. Appl. Crystallogr. 30, 1022–1025 (1997)

    Article  CAS  Google Scholar 

  26. Jones, T., Zou, J.-Y., Cowan, S. & Kjeldgaard, M. Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Crystallogr. A 47, 110–119 (1991)

    Article  Google Scholar 

  27. Winn, M. D., Isupov, M. N. & Murshudov, G. N. Use of TLS parameters to model anisotropic displacements in macromolecular refinement. Acta Crystallogr. D 57, 122–133 (2001)

    Article  CAS  Google Scholar 

  28. Laskowski, R. A. et al. PROCHECK: a program to check the stereochemical quality of protein structures. J. Appl. Crystallogr. 26, 283–291 (1993)

    Article  CAS  Google Scholar 

  29. Carson, M. Ribbons. Methods Enzymol. 277, 493–505 (1997)

    Article  CAS  Google Scholar 

  30. Kraulis, P. J. A program to produce both detailed and schematic plots of protein structures. J. Appl. Crystallogr. 24, 946–950 (1991)

    Article  Google Scholar 

Download references

Acknowledgements

We thank C. Ogata and M. Becker for assistance at beamlines X4A and X25, respectively, of NSLS at Brookhaven National Laboratory; A. Ullrich for supplying a human HER2 complementary DNA; P. Longo for technical assistance; T. Garrett, S. Yokoyama and colleagues for supplying preprints in advance of publication; S. Yokoyama for coordinates of the EGF–EGFR complex; M. Lemmon, K. Ferguson, M. Amzel, J. Berg, S. Bouyain and W. Yang for discussion and comments on the manuscript; A. Guarne for help with figures; and N. Davidson for assistance with Herceptin. This work was supported by the NIH and the HHMI.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Daniel J. Leahy.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cho, HS., Mason, K., Ramyar, K. et al. Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature 421, 756–760 (2003). https://doi.org/10.1038/nature01392

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature01392

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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