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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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Author information

Author notes

  1. Huey-Sheng Shieh, Ravi G. Kurumbail, Anna M. Stevens, Roderick A. Stegeman, Eric J. Sturman, Jina Y. Pak and William C. Stallings: Medicinal and Structural Chemistry

  2. Arthur J. Wittwer, Roger C. Wiegand and Barry C. Holwerda: Infectious Diseases, and

  3. Mark O. Palmier: Biological Sciences, Monsanto/Searle, Searle Discovery Research, 700 Chesterfield Parkway North, St Louis, Missouri 63198, USA

Affiliations

  1. Departments of Medicinal and Structural Chemistry, Monsanto/Searle, Searle Discovery Research, 700 Chesterfield Parkway North, St Louis, Missouri, 63198, USA

    • Huey-Sheng Shieh
    • , Ravi G. Kurumbail
    • , Anna M. Stevens
    • , Roderick A. Stegeman
    • , Eric J. Sturman
    • , Jina Y. Pak
    • , Barry C. Holwerda
    •  & William C. Stallings
  2. Infectious Diseases, Monsanto/Searle, Searle Discovery Research, 700 Chesterfield Parkway North, St Louis, Missouri, 63198, USA

    • Arthur J. Wittwer
    •  & Roger C. Wiegand
  3. Biological Sciences, Monsanto/Searle, Searle Discovery Research, 700 Chesterfield Parkway North, St Louis, Missouri, 63198, USA

    • Mark O. Palmier

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

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