Subjects

Abstract

HERPESVIRUSES encode a serine protease1,2 that specifically cleaves assembly protein3. This protease is critical for replication4, and represents a new target for antiviral drug design5. Here we report the three-dimensional structure of the protease from human cytomegalovirus (hCMV) at 2.27 Å resolution. The structure reveals a unique fold and new catalytic strategy for cleavage. The monomer fold of the enzyme, a seven-stranded β-barrel encircled by a chain of helices that form the carboxy terminus of the molecule, is unrelated to those observed in classic serine proteases such as chymotrypsin and subtilisin. The serine nucleo-phile at position 132 is activated by two juxtaposed histidine residues at positions 63 and 157. Dimerization, which seems to be necessary for activity6,7, is observed in the crystals. Correlations of the structure with the sequences of herpesvirus proteases1,5,8 suggest that dimerization may confer specificity and recognition in substrate binding.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , , , & Proc. Natl Acad. Sci. USA 88, 10792–10796 (1991).

  2. 2.

    & J. Virol. 65, 5149–5156 (1991).

  3. 3.

    & J. Virol. 10, 1044–1052 (1972).

  4. 4.

    , & J. Virol. 45, 1056–1064 (1983).

  5. 5.

    , & Perspect. Drug Discov. Design 2, 413–426 (1994).

  6. 6.

    et al. J. Biol. Chem. 271, 7445–7449 (1996).

  7. 7.

    , , , & Biochemistry 35, 5300–5307 (1996).

  8. 8.

    , , & Biochem. Biophys. Res. Commun. 203, 472–478 (1994).

  9. 9.

    , & J. Mol. Biol. 236, 1382–1400 (1994).

  10. 10.

    et al. J. Biol. Chem. 269, 25911–25915 (1994).

  11. 11.

    , , & J. Virol. 67, 7360–7372 (1993).

  12. 12.

    et al. J. Biol. Chem. 269, 12672–12676 (1994).

  13. 13.

    , , , & J. Mol. Biol. 89, 73–101 (1974).

  14. 14.

    , & Eur. J. Biochem. 166, 673–692 (1987).

  15. 15.

    et al. J. Biol. Chem. 268, 25449–25454 (1993).

  16. 16.

    et al. J. Virol. 68, 2937–2946 (1994).

  17. 17.

    J. Appl. Crystallogr. 16, 548–558 (1983).

  18. 18.

    , & Protein Sci. 1, 1244–1253 (1992).

  19. 19.

    , , , & J. Biol. Chem. 270, 28642–28646 (1995).

  20. 20.

    Adv. Protein Chem. 34, 167–339 (1981).

  21. 21.

    & J. Biol. Chem. 265, 6528–6531 (1990).

  22. 22.

    in Proceedings of the CCP4 Study Weekend: Data Collection Processing (SERC Daresbury Laboratory, Warrington, 1993).

  23. 23.

    & Methods Enzymol. (in the press).

  24. 24.

    , , & Acta Crystallogr. A47, 110–119 (1991).

  25. 25.

    , & Science 235, 458–460 (1987).

  26. 26.

    et al. J. Virol. 67, 497–506 (1993).

  27. 27.

    et al. J. Virol. 68, 3742–3752 (1994).

  28. 28.

    , , & J. Appl. Crystallogr. 26, 283–291 (1993).

  29. 29.

    , , , & J. Virol. 69, 4524–4528 (1995).

  30. 30.

    J. Appl. Crystallogr. 24, 946–950 (1991).

Download references

Author information

Author notes

    • Huey-Sheng Shieh
    • , Ravi G. Kurumbail
    • , Anna M. Stevens
    • , Roderick A. Stegeman
    • , Eric J. Sturman
    • , Jina Y. Pak
    •  & William C. Stallings

    Medicinal and Structural Chemistry

    • Arthur J. Wittwer
    • , Roger C. Wiegand
    •  & Barry C. Holwerda

    Infectious Diseases, and

    • Mark O. Palmier

    Biological Sciences, Monsanto/Searle, Searle Discovery Research, 700 Chesterfield Parkway North, St Louis, Missouri 63198, USA

Affiliations

  1. Departments of

    • Huey-Sheng Shieh
    • , Ravi G. Kurumbail
    • , Anna M. Stevens
    • , Roderick A. Stegeman
    • , Eric J. Sturman
    • , Jina Y. Pak
    • , Arthur J. Wittwer
    • , Mark O. Palmier
    • , Roger C. Wiegand
    • , Barry C. Holwerda
    •  & William C. Stallings

Authors

  1. Search for Huey-Sheng Shieh in:

  2. Search for Ravi G. Kurumbail in:

  3. Search for Anna M. Stevens in:

  4. Search for Roderick A. Stegeman in:

  5. Search for Eric J. Sturman in:

  6. Search for Jina Y. Pak in:

  7. Search for Arthur J. Wittwer in:

  8. Search for Mark O. Palmier in:

  9. Search for Roger C. Wiegand in:

  10. Search for Barry C. Holwerda in:

  11. Search for William C. Stallings in:

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/383279a0

Further reading

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.