3-DIMENSIONAL STRUCTURE OF HUMAN CYTOMEGALOVIRUS PROTEASE

HERPESVIRUSES encode a serine protease(1,2) that specifically cleaves assembly protein(3). This protease is critical for replication(4), and represents a new target for antiviral drug design(5). Here we report the three-dimensional structure of the protease from human cytomegalov irus (hCMV) at 2.27 Angstrom resolution. The structure reveals a uniqu e fold and new catalytic strategy for cleavage. The monomer fold of th e enzyme, a seven-stranded beta-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 subtili sin. The serine nucleophile at position 132 is activated by two juxtap osed histidine residues at positions 63 and 157. Dimerization, which s eems to be necessary for activity(6,7), is observed in the crystals. C orrelations of the structure with the sequences of herpesvirus proteas es(1,5,8) suggest that dimerization may confer specificity and recogni tion in substrate binding.