The HCMV Protease Project

Human cytomegalovirus (HCMV), a herpesvirus, infects most of the population and can cause severe health problems in immuno-suppressed and immuno-comprised individuals. HCMV protease is required for the life cycle of the virus, and is therefore a promising target for the development of novel anti-herpes agents.

The protease is a serine protease, but shares no sequence homology to other serine proteases (chymotrypsin, subtilisin for example). In fact, no cellular homologs of this viral protease have been identified so far, even with the knowledge of the complete genome sequences of various organisms.

Major findings from this project

HCMV protease belongs to a new class of serine proteases.

The protease has a novel Ser-His-His catalytic triad.

A peptidomimetic inhibitor binds the protease in a conserved fashion as in other serine proteases.

There are large conformational changes in the protease upon inhibitor binding (induced-fit behavior).

The protease is a dimer, with an extensive interface between the monomers.

Publications from this project

L. Tong, C. Qian, M.-J. Massariol, P. R. Bonneau, M. G. Cordingley & L. Lagacé. (1996). A new serine-protease fold revealed by the crystal structure of human cytomegalovirus protease. Nature, 383, 272-275. Medline
L. Tong, C. Qian, W. Davidson, M.-J. Massariol, P. R. Bonneau, M. G. Cordingley & L. Lagacé. (1997). Experiences from the structure determination of human cytomegalovirus protease. Acta Cryst. D53, 682-690.
L. Tong, C. Qian, M.-J. Massariol, R. Deziel, C. Yoakim & L. Lagacé. (1998). Conserved mode of peptidomimetic inhibition and substrate recognition of human cytomegalovirus protease. Nature Struct. Biol. 5, 819-826. Medline
C. Qian, L. Lagacé, M.-J. Massariol, C. Chabot, C. Yoakim, R. Deziel & L. Tong. (2000). A rational approach towards successful crystallization and crystal treatment of human cytomegalovirus protease and its inhibitor complex. Acta Cryst. D56, 175-180.
R. Khayat, R. Batra, M.-J. Massariol, L. Lagace & L. Tong. (2001). Investigating the role of histidine157 in the catalytic activity of human cytomegalovirus protease. Biochem. 40, 6344-6351.
R. Batra, R. Khayat & L. Tong. (2001). Molecular mechanism for dimerization to regulate the catalytic activity of human cytomegalovirus protease. Nature Struct. Biol. 8, 810-817.
R. Khayat, R. Batra & L. Tong. (2001). Structural studies of herpesvirus proteases. Protein and Peptide Lett. 8, 333-342.
L. Tong. (2002). Viral proteases. Chem. Rev.. 102, 4609-4626. Reprint(PDF)
R. Khayat, R. Batra, C. Qian, T. Halmos, M. Bailey & L. Tong. (2003). Structural and biochemical studies of inhibitor binding to human cytomegalovirus protease. Biochem. 42, 885-891.
R. Khayat, R. Batra, G.A. Bebernitz, M.W. Olson & L. Tong. (2004). Characterization of the monomer-dimer equilibrium of human cytomegalovirus protease by kinetic methods. Biochem. 43, 316-322.

Funding for this project

NIH R01 AI46139 (1999-2004)