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:

NMR structure of human erythropoietin and a comparison with its receptor bound conformation

Nature Structural Biology volume 5, pages 861–866 (1998)Cite this article

Abstract

The solution structure of human erythropoietin (EPO) has been determined by nuclear magnetic resonance spectroscopy and the overall topology of the protein is revealed as a novel combination of features taken from both the long-chain and short-chain families of hematopoietic growth factors. Using the structure and data from mutagenesis studies we have elucidated the key physiochemical properties defining each of the two receptor binding sites on the EPO protein. A comparison of the NMR structure of the free EPO ligand to the receptor bound form, determined by X-ray crystallography, reveals conformational changes that may accompany receptor binding.

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
Figure 2: a, The average minimized NMR structure of MKLysEPO.
Figure 3: Surface representations of the a, high and b, low affinity receptor binding sites of MKLysEPO.
Figure 4: Best fit superposition of the average minimized NMR structure of MKLysEPO (blue) and the X-ray structure (red) of LysEPO(P121N,P122S) from the 2:1 receptor bound complex16.

Similar content being viewed by others

Accession codes

Accessions

Protein Data Bank

References

  1. Graber, S.E. & Krantz, S.B. Annu. Rev. Med. 29, 51 (1978).

    Article  CAS  Google Scholar 

  2. Youssoufian, H., Longmore, G., Neumann, D., Yoshimura, A. & Lodish, H.F. Blood 81, 2223–2223 (1993).

    CAS  PubMed  Google Scholar 

  3. Markham, A. & Bryson, H.M. Drugs 49, 232–254 (1995).

    Article  CAS  Google Scholar 

  4. Lin, F.K. et al. Proc. Natl. Acad. Sci. USA 82, 7580–7584 (1985).

    Article  CAS  Google Scholar 

  5. Narhi, L.O. et al. J. Biol. Chem. 266, 23022–23026 (1991).

    CAS  PubMed  Google Scholar 

  6. Altieri, A.S., Hinton, D.P. & Byrd, R.A. J. Am. Chem. Soc. 117, 7566–7567 (1995).

    Article  CAS  Google Scholar 

  7. Sprang, S.R. & Bazan, J.F. Curr. Opin. Struct. Biol. 3, 815–827 (1993).

    Article  CAS  Google Scholar 

  8. Harris, N.L., Presnell, S.R. & Cohen, F.E. J. Mol. Biol. 236, 1356–1368 (1994).

    Article  CAS  Google Scholar 

  9. Wishart, D.S. & Sykes, B.D. J. Biomol. NMR 4, 171–180 (1994).

    Article  CAS  Google Scholar 

  10. Elliott, S. et al. Blood 87, 2702–2713 (1996).

    CAS  PubMed  Google Scholar 

  11. Wen, D., Boissel, J.P., Showers, M., Ruch, B.C. & Bunn, H.F. J. Biol. Chem. 269, 22839–22846 (1994).

    CAS  PubMed  Google Scholar 

  12. Zhang, F. et al. Nature 387, 206–209 (1997).

    Article  CAS  Google Scholar 

  13. Elliott, S., Lorenzini, T., Chang, D., Barzilay, J. & Delorme, E. Blood 89, 493–502 (1997).

    CAS  PubMed  Google Scholar 

  14. Bittorf, T., Jaster, R. & Brock, J. FEBS Lett.. 336, 133–136 (1993).

    Article  CAS  Google Scholar 

  15. Matthews, D.J., Topping, R.S., Cass, R.T. & Giebel, L.B. Proc. Natl. Acad. Sci. USA 93, 9471–9476 (1996).

    Article  CAS  Google Scholar 

  16. Syed, R.S. et al. Nature, in the press (1998).

  17. de, V.-A.M., Ultsch, M. & Kossiakoff, A.A. Science 255, 306–312 (1992).

    Article  Google Scholar 

  18. Bazan, J.F. ImmunoL. Today 11, 350–354 (1990).

    Article  CAS  Google Scholar 

  19. Robinson, R.C. et al. Cell 77, 1101–1116 (1994).

    Article  CAS  Google Scholar 

  20. Xu, G.Y. et al. J. Mol. Biol. 268, 468–481 (1997).

    Article  CAS  Google Scholar 

  21. Kay, L.E. Prog. Biophys. Mol. Biol. 63, 277–299 (1995).

    Article  CAS  Google Scholar 

  22. Zink, T. et al. Biochemistry 33, 8453–8463 (1994).

    Article  CAS  Google Scholar 

  23. Kuboniwa, H., Grzesiek, S., Delaglio, F. & Bax, A. J. Biomol. NMR 4, 871–878 (1994).

    Article  CAS  Google Scholar 

  24. Farrow, N.A. et al. Biochemistry 33, 5984–6003 (1994).

    Article  CAS  Google Scholar 

  25. Bagby, S., Harvey, T.S., Eagle, S.G., Inouye, S. & Ikura, M. Structure 2, 107–122 (1994).

    Article  CAS  Google Scholar 

  26. Brunger, A.T. X-PLOR 3.1 Manual (Yale University Press, New Haven, Connecticut; 1992).

    Google Scholar 

  27. Esnouf, R.M. J. Mol. Graphics 15, 133–138 (1997).

    Google Scholar 

  28. Ghose, A. & Crippen, G. J. Comp. Chem. 7, 565–577 (1986).

    Article  CAS  Google Scholar 

  29. Laskowski, R.A., MacArthur, M.W., Moss, D.S. & Thornton, J.M. J. Appl. Crystallogr. 26, 283–291 (1993).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge T. Boone for providing the original LysEPO clone, G. Stearns and G. Rogers (AMGEN) for help in production of labeled protein and L.E. Kay (University of Toronto) for initial NMR data collection facilities. We also thank N.A. Farrow (University of Toronto) and J. Cavanagh (New York State Dept. Health) for discussions on NMR relaxation data analysis, and S. Elliott and T. Osslund (AMGEN) for many useful discussions and critical reading of the manuscript.

Author information

Authors and Affiliations

  1. Amgen Inc, One Amgen Center Drive, Thousand Oaks, 91320, California, USA

    Janet C. Cheetham, Duncan M. Smith, Kenneth H. Aoki, Janice L. Stevenson, Thomas J. Hoeffel, Rashid S. Syed, Joan Egrie & Timothy S. Harvey.

Authors
  1. Janet C. Cheetham
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Duncan M. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kenneth H. Aoki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Janice L. Stevenson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thomas J. Hoeffel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rashid S. Syed
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Joan Egrie
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Timothy S. Harvey.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Janet C. Cheetham.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cheetham, J., Smith, D., Aoki, K. et al. NMR structure of human erythropoietin and a comparison with its receptor bound conformation . Nat Struct Mol Biol 5, 861–866 (1998). https://doi.org/10.1038/2302

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/2302

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