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:

Molecular basis of crossreactivity and the limits of antibody–antigen complementarity

Nature volume 365, pages 859–863 (1993)Cite this article

Abstract

TWO major unanswered questions concerning the specificity of antibodies are: how do structurally different antigens bind with high affinity to the same antibody, and what are the limits of the antibody combining site complementarity and flexibility that contribute to such crossreactivity? We report here a comparative analysis of the X-ray structures of five conformationally different steroids in complex with the Fab′ fragment of an anti-progesterone antibody DB3 at 2.7 Å. This antibody is unable to complement completely the shape of the hydrophobic antigen so that crossreactivity occurs with other ligands without major structural rearrangements of the binding site. Antigen specificity can be explained through conserved interactions of DB3 with the steroid D-ring, whereas some of the crossreactivity is realized through different binding orientations of the steroid skeleton that place the A-ring into alternative pockets on the antibody surface. The restricted gene usage of the VGAM3.8 family in the generation of anti-progesterone monoclonal antibodies1,2 may be explained by the specific interaction of VH hallmark residues with the steroid D-ring. This first detailed structure of steroid interactions with a protein could be applied to the understanding of general mechanisms of steroid recognition as well as in the design of specific binding sites for small hydrophobic ligands.

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

Similar content being viewed by others

References

  1. Deverson, E., Berek, C., Taussig, M. J. & Feinstein, A. Eur. J. Immun. 17, 9–13 (1987).

    Article  CAS  Google Scholar 

  2. Sims, M. J., Krawinkel, U. & Taussig, M. J. J. Immun. 149, 1642–1648 (1992).

    CAS  PubMed  Google Scholar 

  3. Wright, L. J. et al. Nature 295, 415–417 (1982).

    Article  ADS  CAS  Google Scholar 

  4. Ellis, S. T. et al. J. Endocrin. 118, 69–80 (1988).

    Article  CAS  Google Scholar 

  5. Stura, E. A. et al. Immunology 62, 511–521 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Landsteiner, K. The Specificity of Serological Reactions (Dover, New York, 1962).

    Google Scholar 

  7. van Regenmortel, M. H. V. Immun. Today 10, 266–272 (1989).

    Article  CAS  Google Scholar 

  8. Arevalo, J. H., Stura, E. A., Taussig, M. J. & Wilson, I. A. J. molec. Biol. 231, 103–118 (1993).

    Article  CAS  Google Scholar 

  9. Duax, W. L. & Norton, D. A. Atlas of Steroid Structures Vol. 1 (Plenum, New York, 1975).

    Book  Google Scholar 

  10. Griffin, J. F., Duax, W. L. & Weeks, C. M. Atlas of Steroid Structures Vol. 2 (Plenum, New York, 1984).

    Book  Google Scholar 

  11. Burley, S. K. & Petsko, G. A. Science 229, 23–28 (1983).

    Article  ADS  Google Scholar 

  12. Wilson, I. A. & Stanfield, R. L. Curr. Opin. struct. Biol. 3, 113–118 (1993).

    Article  CAS  Google Scholar 

  13. Stanfield, R. L., Takimoto-Kamimura, M., Rini, J. M., Profy, A. T. & Wilson I. A. Structure (in the press).

  14. Rini, J. M., Schulze-Gahmen, U. & Wilson, I. A. Science 255, 959–965 (1992).

    Article  ADS  CAS  Google Scholar 

  15. Lee, B. & Richards, F. M. J. molec. Biol. 55, 376–400 (1971).

    Article  Google Scholar 

  16. Bohacek, R. S. & McMartin, C. J. med. Chem. 35, 1671–1684 (1992).

    Article  CAS  Google Scholar 

  17. Mudgett-Hunter, M., Anderson, W., Haber, E. & Margolies, M. N. Molec. Immun. 22, 477–488 (1985).

    Article  CAS  Google Scholar 

  18. Taussig, M. J. et al. Immunology 72, 471–480 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Kabat, E. A., Wu, T. T., Perry, H. M., Gottesman, K. S. & Foeller, C. Sequences of Proteins of Immunological Interest 5th edn (National Institutes of Health, Bethesda, 1991).

    Google Scholar 

  20. Berek, C. & Milstein, C. Immunol. Rev. 96, 23–41 (1987).

    Article  CAS  Google Scholar 

  21. Alzari, P. M. et al. EMBO J. 9, 3807–3814 (1990).

    Article  CAS  Google Scholar 

  22. Parhami-Seren, B., Kussie, P. H., Strong, R. K. & Margolies, M. N. J. Immun. 150, 1829–1837 (1993).

    CAS  PubMed  Google Scholar 

  23. Lascombe, M-B., Alzari, P. M., Poljak, R. J. & Nisonoff, A. Proc. natn. Acad. Sci. U.S.A. 89, 9429–9433 (1992).

    Article  ADS  CAS  Google Scholar 

  24. Evans, R. M. Science 240, 889–895 (1988).

    Article  ADS  CAS  Google Scholar 

  25. Baulieu, E-E. Science 245, 1351–1357 (1989).

    Article  ADS  CAS  Google Scholar 

  26. Strickler, R. C., Covey, D. F. & Tobias, B. Biochemistry 19, 4950–4954 (1980).

    Article  CAS  Google Scholar 

  27. Luu-The, V. et al. Biochemistry 36, 8861–8865 (1991).

    Article  Google Scholar 

  28. Brunger, A. T. X-PLOR version 2.1 (Yale University, 1990).

    Google Scholar 

  29. Jones, A. T. J. appl. Crystallogr. 11, 268–272 (1978).

    Article  CAS  Google Scholar 

  30. Kabat, E. A. & Wu, T. T. J. Immun. 147, 1709–1719 (1991).

    CAS  PubMed  Google Scholar 

  31. Ferrin, T. E., Huang, C. C., Jarvis, L. E. & Langridge, R. J. molec. Graphics 6, 13–27 (1988).

    Article  CAS  Google Scholar 

  32. Connolly, M. L. Science 221, 709–713 (1983).

    Article  ADS  CAS  Google Scholar 

  33. Gelin, B. R. & Karplus, M. Biochemistry 18, 1256–1268 (1979).

    Article  CAS  Google Scholar 

  34. Upson, C. et al. IEEE comput. Graph. Applic. 9, 30–42 (1989).

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular Biology, The Scripps Research Institute, 10666 North Torrey Pines Road, La Jolla, California, 92037, USA

    Jairo H. Arevalo & Ian A. Wilson

  2. Laboratory of Structural Studies, Department of Immunology, The AFRC Babraham Institute, Babraham, Cambridge, CB2 4AT, UK

    Michael J. Taussig

Authors
  1. Jairo H. Arevalo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael J. Taussig
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ian A. Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Arevalo, J., Taussig, M. & Wilson, I. Molecular basis of crossreactivity and the limits of antibody–antigen complementarity. Nature 365, 859–863 (1993). https://doi.org/10.1038/365859a0

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/365859a0

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

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