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:

X-ray structure of phospholipase A2 complexed with a substrate-derived inhibitor

Nature volume 347, pages 689–691 (1990)Cite this article

Abstract

PHOSPHOLIPASES A2 play a part in a number of physiologically important cellular processes such as inflammation, blood platelet aggregation and acute hypersensitivity1,2. These processes are all initiated by the release of arachidonic acid from cell membranes which is catalysed by intracellular phospholipases A2 and followed by conversion of arachidonic acid to prostaglandins, leukotrienes or thromboxanes3. An imbalance in the production of these com-pounds can lead to chronic inflammatory diseases such as rheumatoid arthritis and asthma. Inhibitors of phospholipase A2 might therefore act to reduce the effects of inflammation, so structural information about the binding of phospholipase A2 to its substrates could be helpful in the design of therapeutic drugs. The three-dimensional structure is not known for any intracellular phospholipase A2, but these enzymes share significant sequence homology4–6 with secreted phospholipases, for which some of the structures have been determined7–10. Here we report the structure of a complex between an extracellular phospholipase A2 and a competitively inhibiting substrate analogue, which reveals considerable detail about the interaction and suggests a mechanism for catalysis by this enzyme.

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. Hirata, F. & Axelrod, J. Science 209, 1082–1090 (1980).

    Article  ADS  CAS  Google Scholar 

  2. Vadas, P. & Pruzanski, W. Lab. Invest. 4, 391–404 (1986).

    Google Scholar 

  3. Flower, R. Tr. pharmacol. Sci. 2, 186–188 (1981).

    Article  CAS  Google Scholar 

  4. Seilhamer, J. J. et al. J. biol. Chem. 264, 5335–5338 (1989).

    CAS  PubMed  Google Scholar 

  5. Kramer, R. M. et al. J. biol. Chem. 264, 5768–5775 (1989).

    CAS  PubMed  Google Scholar 

  6. Mizushima, H. et al. J. Biochem. 105, 520–525 (1989).

    Article  CAS  Google Scholar 

  7. Dijkstra, B. W., Kalk, K. H., Hol, W. G. J. & Drenth, J. J. molec. Biol. 147, 93–123 (1981).

    Article  Google Scholar 

  8. Dijkstra, B. W., Renetseder, R., Kalk, K. H., Hol, W. G. J. & Drenth, J. J. molec. Biol. 168, 163–179 (1983).

    Article  CAS  Google Scholar 

  9. Brunie, S., Bolin, J., Gewirth, P. & Sigler, P. B. J. biol. Chem. 260, 9742–9747 (1985).

    CAS  PubMed  Google Scholar 

  10. Renetseder, R., Brunie, S., Dijkstra, B. W., Drenth, J. & Sigler, P. B. J. biol. Chem. 260, 11627–11634 (1985).

    CAS  PubMed  Google Scholar 

  11. de Haas, G. H., Dijkman, R., van Oort, M. G. & Verger, R. Biochim. biophys. Acta 1043, 75–82 (1990).

    Article  CAS  Google Scholar 

  12. Kuipers, O. P. et al. Science 244, 82–85 (1989).

    Article  ADS  CAS  Google Scholar 

  13. Kuipers, O. P., Dijkman, R., Pals, C. E. G. M., Verheij, H. M. & de Haas, G. H. Protein Engng 2, 467–471 (1989).

    Article  CAS  Google Scholar 

  14. Hitchcock, P. B., Mason, R., Thomas, K. M. & Shipley, G. G. Proc. natn. Acad. Sci. U.S.A. 71, 3036–3040 (1974).

    Article  ADS  CAS  Google Scholar 

  15. Seelig, J. & Browning, J. L. FEBS Lett. 92, 41–44 (1978).

    Article  CAS  Google Scholar 

  16. Dijkstra, B. W., Kalk, K. H. & Drenth, J. Nature 289, 604–606 (1981).

    Article  ADS  CAS  Google Scholar 

  17. Verheij, H. M. et al. Biochemistry 19, 743–750 (1980).

    Article  CAS  Google Scholar 

  18. Volwerk, J. J., Dedieu, A. G. R., Verheij, H. M., Dijkman, R. & de Haas, G. H. Reel. Trav. Chim. Pays-Bas 98, 214–220 (1979).

    Article  CAS  Google Scholar 

  19. Carter, P., Bedouelle, H. & Winter, G. Nucleic Acids Res. 13, 4431–4443 (1985).

    Article  CAS  Google Scholar 

  20. Kramer, W. et al. Nucleic Acids Res. 12, 9441–9456 (1984).

    Article  CAS  Google Scholar 

  21. Sanger, F., Nicklen, S. & Coulson, A. R. Proc. natn. Acad. Sci. U.S.A. 74, 5463–5467 (1977).

    Article  ADS  CAS  Google Scholar 

  22. Dijkman, R., Dekker, N. & de Haas, G. H. Biochim. biophys. Acta 1043, 67–74 (1990).

    Article  CAS  Google Scholar 

  23. Read, R. Acta crystallogr. Sect. A 42, 140–149 (1986).

    Article  Google Scholar 

  24. Crowther, R. A. in The Molecular Replacement Method (ed. Rossman, M. G.) 173–178 (Gordon & Breach, New York, 1972).

    Google Scholar 

  25. Crowther, R. A. & Blow, D. M. Acta crystallogr. 23, 544–548 (1967).

    Article  CAS  Google Scholar 

  26. Tronrud, D. E., Ten Eyck, L. F. & Matthews, B. W. Acta crystallogr. Sect. A 43, 489–501 (1987).

    Article  Google Scholar 

  27. Jones, T. A. Meth. Enzym. 115, 157–171 (1985).

    Article  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Oscar P. Kuipers, Ruud Dijkman and Gerard H. de Haas: Department of Enzymology and Protein Engineering, University of Utrecht, Center for Biomembranes and Lipid Enzymology, PO Box 80054, 3508 TB Utrecht, The Netherlands

Authors and Affiliations

  1. Laboratory of Chemical Physics, University of Groningen, Nijenborgh 16, 9747 AG, Groningen, The Netherlands

    Marjolein M. G. M. Thunnissen, Eiso AB, Kor H. Kalk , Jan Drenth, Bauke W. Dijkstra, Oscar P. Kuipers, Ruud Dijkman, Gerard H. de Haas & Hubertus M. Verheij

Authors
  1. Marjolein M. G. M. Thunnissen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eiso AB
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kor H. Kalk
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jan Drenth
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bauke W. Dijkstra
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Oscar P. Kuipers
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ruud Dijkman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gerard H. de Haas
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hubertus M. Verheij
    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

Thunnissen, M., AB, E., Kalk , K. et al. X-ray structure of phospholipase A2 complexed with a substrate-derived inhibitor. Nature 347, 689–691 (1990). https://doi.org/10.1038/347689a0

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/347689a0

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