UNIQUE FOLD AND ACTIVE-SITE IN CYTOMEGALOVIRUS PROTEASE

HUMAN herpesviruses are responsible for a variety of diseases. They ar e divided into three subfamilies: alpha includes herpes simplex viruse s (HSV-1 and HSV-2) and varicella-zoster virus (VZV); beta includes cy tomegalovirus (CMV) and human herpes-virus-6 (HHV-6); and gamma includ es Epstein-Barr virus (EBV). Each virus encodes a serine protease that is essential for its replication(1-14) and is a potential target for therapeutic intervention. Human CMV is a ubiquitous opportunistic path ogen that can result in life-threatening infections in congenitally in fected infants, immunocompromised individuals and immunosuppressed can cer or transplant patients(15). Here we report the crystal structure o f human CMV protease at 2.5 Angstrom 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 thir d member is a histidine instead of an aspartic acid, or possibly a cat alytic tetrad consisting of a serine, two histidines and an aspartic a cid. An unusual dimer interface that is important to the protease acti vity has also been identified.