Abstract
HUMAN herpesviruses are responsible for a variety of diseases. They are divided into three subfamilies: alpha includes herpes simplex viruses (HSV-1 and HSV-2) and varicella-zoster virus (VZV); beta includes cytomegalovirus (CMV) and human herpes-virus-6 (HHV-6); and gamma includes Epstein–Barr virus (EBV).Each virus encodes a serine protease that is essential for its replication1–14and is a potential target for therapeutic intervention. Human CMV is a ubiquitous opportunistic pathogen that can result in life-threatening infections in congenitally infected infants, immunocompromised individuals and immuno-suppressed cancer or transplant patients15. Here we report the crystal structure of human CMV protease at 2.5 Å resolution. The structure reveals a fold that has not been reported for any other serine protease, and an active site consisting of a novel catalytic triad in which the third member is a histidine instead of an aspartic acid, or possibly a catalytic tetrad consisting of a serine, two histidines and an aspartic acid. An unusual dimer interface that is important to the protease activity has also been identified.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Liu, F. & Roizman, B. J. Virol. 65, 5149–5156 (1991).
Gao, M. et al. J. Virol. 68, 3702–3712 (1994).
Liu, F. & Roizman, B. J. Virol. 67, 1300–1309 (1993).
Weinheimer et al. J. Virol. 67, 5813–5822 (1993).
Liu, F. & Roizman, B. Proc. Natl Acad. Sci. USA 89, 2076–2080 (1992).
Welch, A. R., McNally, L. M., Hall, M. R. T. & Gibson, W. J. Virol. 67, 7360–7372 (1993).
Cox, G. A., Wakulchik, M., Sassmannshausen, L. M., Gibson, W. & Villarreal, E. C. J. Virol. 69, 4524–4528 (1995).
Stevens, J. T. et al. Eur. J. Biochem. 226, 361–367 (1994).
Burck, P. J. et al. J. Virol. 68, 2937–2946 (1994).
Holwerda, B. C. et al. J. Biol. Chem. 269, 25911–25915 (1994).
Baum, E. Z. et al. J. Virol. 67, 497–506 (1993).
O'Boyle II, D. R., Wager-Smith, K., Stevens III, J. T. & Weinheimer, S. P. J. Biol. Chem. 270, 4753–4758 (1993).
Welch, A. R., Villarreal, E. C. & Gibson, W. J. Virol. 69, 341–347 (1993).
Dilanni, C. L. et al. J. Biol. Chem. 268, 25449–25454 (1993).
Alford, C. A. & Britt, W. J. in Virology 2nd edn (eds Knipe, D. M. and Fields, B. N.) 1981–2010 (Raven, New York, 1990).
Chothia, C. & Janin, J. Biochemistry 21, 3955–3965 (1982).
Margosiak, S. A., Vanderpool, D. L., Sisson, W., Pinko, C. & Kan, C. Biochemistry 35, 5300–5307 (1995).
Darke, P. L. et al. J. Biol. Chem. 271, 7445–7449 (1996).
Perona, J. J. & Craik, C. S. Protein Sci. 4, 337–360 (1995).
Otwinowski, Z. in Data Collection and Processing (eds Sawyer, L., Isaacs, N. & Bailey, S.) 56–62 (Daresbury Laboratory, Warrington, 1993).
Howard, A. J. et al. J. Appl. Crystallogr. A47, 110–119 (1994).
Collaborative Computational Project Acta Crystallogr. D50, 760–763 (1994).
Otwinowski, Z. in Isomorphous Replacement and Anomalous Scattering (eds Wolff, W., Evans, P. R. & Leslie, A. G. W.) 80–86 (Daresbury Laboratory, Warrington, 1991).
McKee, D. E. Practical Protein Crystallography (Academic, San Diego, 1993).
Brunger, A. T., Kuriyan, J. & Karplus, M. Science 235, 458–460 (1987).
Laskowski, R. A., MacArthur, M. W., Morris, A. L. & Thornton, J. M. J. Appl. Crystallogr. 26, 283–291 (1993).
Kraulis, P. J. Appl. Crystallogr. 24, 946–950 (1991).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Qiu, X., Culp, J., DiLella, A. et al. Unique fold and active site in cytomegalovirus protease. Nature 383, 275–279 (1996). https://doi.org/10.1038/383275a0
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/383275a0
This article is cited by
-
Extensive subunit contacts underpin herpesvirus capsid stability and interior-to-exterior allostery
Nature Structural & Molecular Biology (2016)
-
Inhibition of a viral enzyme by a small-molecule dimer disruptor
Nature Chemical Biology (2009)
-
Antiherpesvirus drugs: a promising spectrum of new drugs and drug targets
Nature Reviews Drug Discovery (2003)
-
Conserved mode of peptidomimetic inhibition and substrate recognition of human cytomegalovirus protease
Nature Structural Biology (1998)
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.