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Unique fold and active site in cytomegalovirus protease

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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.

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Authors and Affiliations

  1. Department of Macromolecular Sciences, SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, King of Prussia, Pennsylvania, 19406, USA

    Xiayang Qiu, Susan S. Hoog, Ward W. Smith & Sherin S. Abdel-Meguid

  2. Department of Protein Biochemistry, SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, King of Prussia, Pennsylvania, 19406, USA

    Jeffrey S. Culp, Brian Hellmig & Cheryl A. Janson

  3. Department of Molecular Genetics, SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, King of Prussia, Pennsylvania, 19406, USA

    Anthony G. DiLella

Authors
  1. Xiayang Qiu
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  2. Jeffrey S. Culp
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  3. Anthony G. DiLella
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  4. Brian Hellmig
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  5. Susan S. Hoog
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  6. Cheryl A. Janson
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  7. Ward W. Smith
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  8. Sherin S. Abdel-Meguid
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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

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  • DOI: https://doi.org/10.1038/383275a0

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