Abstract
HERPESVIRUSES encode a serine protease1,2that 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.
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References
Welch, A. R., Woods, A. S., McNally, L. M., Cotter, R. J. & Gibson, W. Proc. Natl Acad. Sci. USA 88, 10792–10796 (1991).
Liu, F. & Roizman, B. J. Virol. 65, 5149–5156 (1991).
Gibson, W. & Roizman, B. J. Virol. 10, 1044–1052 (1972).
Preston, V. G., Coates, J. A. V. & Rixon, F. J. J. Virol. 45, 1056–1064 (1983).
Gibson, W., Welch, A. R. & Hall, M. R. T. Perspect. Drug Discov. Design 2, 413–426 (1994).
Darke, P. L. et al. J. Biol. Chem. 271, 7445–7449 (1996).
Margosiak, S. A., Vanderpool, D. L., Sisson, W., Pinko, C. & Kan, C. C. Biochemistry 35, 5300–5307 (1996).
Loutsch, J. M., Galvin, N. J., Bryant, M. L. & Holwerda, B. C. Biochem. Biophys. Res. Commun. 203, 472–478 (1994).
Murzin, A. G., Lesk, A. M. & Chothia, C. J. Mol. Biol. 236, 1382–1400 (1994).
Holwerda, B. C. et al. J. Biol. Chem. 269, 25911–25915 (1994).
Welch, A. R., McNally, L. M., Hall, M. R. & Gibson, W. J. Virol. 67, 7360–7372 (1993).
Dilanni, C. L. et al. J. Biol. Chem. 269, 12672–12676 (1994).
Huber, R., Kukla, D., Steigemann, W., Deisenhofer, J. & Jones, A. J. Mol. Biol. 89, 73–101 (1974).
Bode, W., Papamokos, E. & Musil, D. Eur. J. Biochem. 166, 673–692 (1987).
Dilanni, C. L. et al. J. Biol. Chem. 268, 25449–25454 (1993).
Burck, P. J. et al. J. Virol. 68, 2937–2946 (1994).
Connolly, M. L. J. Appl. Crystallogr. 16, 548–558 (1983).
Babe, L. M., Rose, J. & Craik, C. S. Protein Sci. 1, 1244–1253 (1992).
Divita, G., Baillon, J. G., Rittinger, K., Chermann, J. & Goody, R. S. J. Biol. Chem. 270, 28642–28646 (1995).
Richardson, J. S. Adv. Protein Chem. 34, 167–339 (1981).
Liao, D. I. & Remington, S. J. J. Biol. Chem. 265, 6528–6531 (1990).
Otinowski, Z. in Proceedings of the CCP4 Study Weekend: Data Collection Processing (SERC Daresbury Laboratory, Warrington, 1993).
Furey, W. & Swaminathan, S. Methods Enzymol. (in the press).
Jones, T. A., Zou, J. Y., Cowan, S. W. & Kjeldgaard, M. Acta Crystallogr. A47, 110–119 (1991).
Brünger, A. T., Kuriyan, J. & Karplus, M. Science 235, 458–460 (1987).
Baum, E. Z. et al. J. Virol. 67, 497–506 (1993).
Jones, T. R. et al. J. Virol. 68, 3742–3752 (1994).
Laskowski, R. A., MacArthue, M. W., Moss, D. S. & Thornton, J. M. J. Appl. Crystallogr. 26, 283–291 (1993).
Cox, G. A., Wakulchik, M., Sassmannshausen, M., Gibson, W. & Villarreal, E. C. J. Virol. 69, 4524–4528 (1995).
Kraulis, P. J. J. Appl. Crystallogr. 24, 946–950 (1991).
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Shieh, HS., Kurumbail, R., Stevens, A. et al. Three-dimensional structure of human cytomegalovirus protease. Nature 383, 279–282 (1996). https://doi.org/10.1038/383279a0
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DOI: https://doi.org/10.1038/383279a0
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