A NEW SERINE-PROTEASE FOLD REVEALED BY THE CRYSTAL-STRUCTURE OF HUMANCYTOMEGALOVIRUS PROTEASE

HUMAN cytomegalovirus (hCMV), a herpesvirus, infects up to 70% of the general population in the United States and can cause morbidity and mo rtality in immunosuppressed individuals (organ-transplant recipients a nd AIDS patients) and congenitally infected newborns(1). hCMV protease is essential for the production of mature infectious virions, as it p erforms proteolytic processing near the carboxy terminus (M-site) of t he viral assembly protein precursor (for a review, see ref. 2). hCMV p rotease is a serine protease(2), although it has little homology to ot her clans of serine proteases(2,3). Here we report the crystal structu re of hCMV pretense at 2.0 Angstrom resolution, and show that it posse sses a new polypeptide backbone fold. Ser 132 and His 63 are found in close proximity in the active site, confirming earlier biochemical and mutagenesis studies(2). The structure suggests that the third member of the triad is probably His 157. A dimer of the protease with an exte nsive interface is found in the crystal structure. This structure info rmation will help in the design and optimization of inhibitors against herpesvirus proteases.