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Steven Dewhurst, David
Skrincosky and Nanette van Loon
Author contact details
Recently, the crystal structure of the HCMV protease was solved by several groups of investigators, including scientists from Monsanto/Searle (Shieh et al., (1996) Nature, 383, 279), Boehringer Ingelheim (Tong et al., (1996) Nature, 383, 272) SmithKline Beecham (Qiu et al., (1996) Nature, 383, 275) and Agouron Pharmaceuticals (Chen et al. (1996), Cell, 86, 835-843).
A 3-D structure of the HCMV protease can be modelled using the pdb co-ordinates from its structure. Using Chime software (a plug-in for the Netscape browser, available from the CHIME homepage) you can move the structure around to see its overall structure, dimerization, active site etc. Important Note: this won't work without the plug-in being installed on your computer/network.
To manipulate the five images yourself, hold the cursor over each image, press down on the mouse button and move the mouse around.
To clear changes: .
Herpes virus serine proteases
All herpesviruses encode a serine protease enzyme, which acts to cleave the viral assembly
protein. These proteases are closely related and are essential for viral replication;
they, therefore, represent an important potential target for antiviral drugs.
The serine protease and the viral assembly protein are encoded by the same open reading
frame in the viral genome, as a single fusion polypeptide.
The protease recognizes and cleaves a specific sequence found at the 'release site'
between the protease and the assembly protein in the fusion polypeptide, and it also
cleaves at a 'maturation site' at the C-terminus of the assembly protein.
The proteases cleave a peptide bond found between an alanine and a serine, and they are only weakly inhibitable by common serine protease inhibitors such as phenyl methyl sulphonyl fluoride (PMSF) and N-alpha-p-tosyl-L-lysine chloromethyl ketone (TLCK). This suggests that the herpesvirus enzymes might represent a unique class of serine proteases
Human cytomegalovirus (HCMV) serine protease
Structural studies with the HCMV serine protease have substantiated the
theory that the herpes virus enzymes represent a unique class of enzymes.
Monomer subunits
Each of the monomer subunits of the enzyme possesses an overall protein fold that
comprises a seven-stranded beta-barrel core (in yellow) with seven alpha-helices (in
magenta) surrounding it on three sides: click the box here->
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Homodimer
The enzyme forms a homodimer: click the box here->
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Dimerization of the two monomer subunits is required for enzyme activity; this dependence
is surprising, because the interface between the two monomer subunits (dimer interface) is
not close to the active site of the enzyme.
Active site
The active site of the HCMV protease contains an 'active site triad' of serine (Ser132, in
white), click the box here ->
which has been shown to be the catalytic nucleophile of the enzyme, together with two
additional residues (His63, His157, in yellow).click the box here
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Amino acid conservation/alignment
The amino acids in the serine proteases in the herpes viruses studied so far
(including HHV-6 and HHV-7) are highly conserved.
The amino acid identity to the HCMV enzyme is 42% for HHV-6 and 38% for HHV-7
.
The three protein sequences for the serine proteases of HCMV, HHV-6 and HHV-7
are known and can be aligned to show this amino acid conservation and the three
putative active sites (see fig004sdr).
For more details see the article on HHV-6 (txt001sdr).
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