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:

Crystal structure of catechol O-methyltransferase

Abstract

CATECHOL O-methyltransferase (COMT, EC 2.1.1.6) is important in the central nervous system because it metabolizes catecholamine neurotransmitters such as dopamine. The enzyme catalyses the transfer of the methyl group from S-adenosyl-l-methionine (AdoMet) to one hydroxyl group of catechols1–4. COMT also inactivates catechol-type compounds such as l-DOPA. With selective inhibitors of COMT in combination with l-DOPA, a new principle has been realized in the therapy of Parkinson's disease5–9. Here we solve the atomic structure of COMT to 2.0 Å resolution, which provides new insights into the mechanism of the methyl transfer reaction. The co-enzyme-binding domain is strikingly similar to that of an AdoMet-dependent DNA methylase10, indicating that all AdoMet methylases may have a common structure.

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

Similar content being viewed by others

References

  1. Axelrod, J. & Tomchick, R. J. biol. Chem. 233, 702–705 (1958).

    CAS  PubMed  Google Scholar 

  2. Ball, P., Knuppen, R., Haupt, M. & Breuer, H. J. clin. Endocr. 34, 736–746 (1972).

    Article  CAS  Google Scholar 

  3. Borchardt, R. in Enzymatic Basis of Detoxification (ed. Jakoby, W. B.) 43–62 (Academic, New York, 1980).

    Book  Google Scholar 

  4. Guldberg, H. & Marsden, C. Pharmac. Rev. 27, 135–206 (1975).

    CAS  Google Scholar 

  5. Bäckström, R. et al. J. med. Chem. 32, 841–846 (1989).

    Article  Google Scholar 

  6. Borgulya, J., Bruderer, H., Bernauer, K., Zurcher, G. & Da Prada, M. Helv. chim. Acta 72, 952–968 (1989).

    Article  CAS  Google Scholar 

  7. Männistö, P. & Kaakkola, S. Trends pharmac. Sci. 10, 54–56 (1989).

    Article  Google Scholar 

  8. Linden, I.-B. et al. Pharmac. exp. Ther. 247, 289–293 (1988).

    CAS  Google Scholar 

  9. Männistö, P. et al. in Progress in Drug Research (ed. Jucker, E.) 291–350 (Birkhäuser, Basel, 1992).

    Google Scholar 

  10. Cheng, X., Kumar, S., Posfai, J., Pflugrath, J. & Roberts, R. Cell 74, 299–307 (1993).

    Article  CAS  Google Scholar 

  11. Salminen, M. et al. Gene 93, 241–247 (1990).

    Article  CAS  Google Scholar 

  12. Vidgren, J., Tilgmann, C., Lundström, K. & Liljas, A. Proteins 11, 233–236 (1991).

    Article  CAS  Google Scholar 

  13. Lundström, K., Tilgmann, C., Peränen, J., Kalkkinen, N. & Ulmanen, I. Biochim. biophys. Acta 1129, 149–154 (1992).

    Article  Google Scholar 

  14. Eklund, H. et al. J. molec. Biol. 146, 561–587 (1981).

    Article  CAS  Google Scholar 

  15. Jeffery, D. & Roth, J. Biochemistry 26, 2955–2958 (1987).

    Article  CAS  Google Scholar 

  16. Woodard, R., Tsai, M., Floss, H., Crooks, P. & Coward, J. J. biol. Chem. 255, 9124–9127 (1980).

    CAS  PubMed  Google Scholar 

  17. Coward, J., Slisz, E. & Wu, F. Biochemistry 12, 2291–2297 (1973).

    Article  CAS  Google Scholar 

  18. Schultz, E. & Nissinen, E. Biochem. Pharmac. 38, 3953–3956 (1989).

    Article  CAS  Google Scholar 

  19. Creveling, C., Morris, N., Shimizu, H., Ong, H. & Daly, J. Molec. Pharmac. 8, 398–409 (1972).

    CAS  Google Scholar 

  20. Thakker, D., Boehlert, C., Kirk, K., Antkowiak, R. & Creveling, C. J. biol. Chem. 261, 178–184 (1986).

    CAS  PubMed  Google Scholar 

  21. Piedrafita, J., Elorriaga, C., Fernandez-Alvarez, E. & Nieto, O. J. Enzym. Inhib. 4, 43–50 (1990).

    Article  CAS  Google Scholar 

  22. Gomi, T., Tanihara, K., Date, T. & Fujioka, M. Int. J. Biochem. 24, 1639–1649 (1992).

    Article  CAS  Google Scholar 

  23. Howard, A. et al. J. appl. Crystallogr. 20, 383–387 (1987).

    Article  CAS  Google Scholar 

  24. CCP4, A Suite of Programs for Protein Crystallography (SERC (UK) Collaborative Computing Project No. 4, Daresbury Laboratory, Warrington, 1979).

  25. Cowtan, K. & Main, P. Acta crystallogr. D49, 148–157 (1993).

    Article  CAS  Google Scholar 

  26. Jones, T. A., Zou, J.-Y., Cowan, S. & Kjeldgaard, M. Acta crystallogr. A47, 110–119 (1991).

    Article  Google Scholar 

  27. Brunger, A. X-PLOR Version 3.0, A System for Crystallography and NMR (Yale University, CT, 1992).

    Google Scholar 

  28. Lundström, K., Salminen, M., Jalanko, A., Savolainen, R. & Ulmanen, I. DNA Cell Biol. 10, 181–189 (1991).

    Article  Google Scholar 

  29. Bertocci, B. et al. Biochim. biophys. Acta 1080, 103–109 (1991).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vidgren, J., Svensson, L. & Liljas, A. Crystal structure of catechol O-methyltransferase. Nature 368, 354–358 (1994). https://doi.org/10.1038/368354a0

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/368354a0

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