ACTIVE-SITE CAVITY OF HERPESVIRUS PROTEASES REVEALED BY THE CRYSTAL-STRUCTURE OF HERPES-SIMPLEX VIRUS PROTEASE INHIBITOR COMPLEX/

Human herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are respo nsible for herpes labialis (cold sores) and genital herpes, respective ly. They encode a serine protease that is required for viral replicati on, and represent a viable target for therapeutic intervention. Here, we report the crystal structures of HSV-1 and HSV-2 proteases, the lat ter in the presence and absence of the covalently bound transition sta te analog inhibitor diisopropyl phosphate (DIP). The HSV-1 and HSV-2 p rotease structures show a fold that is neither like chymotrypsin nor l ike subtilisin, and has been seen only in the recently determined cyto megalovirus (CMV) and varicella-zoster virus (VZV) protease structures . HSV-1 and HSV-2 proteases share high sequence homology and have almo st identical three-dimensional structures. However, structural differe nces are observed with the less homologous CMV protease, offering a st ructural basis for herpes virus protease ligand specificity. The bound inhibitor identifies the oxyanion hole of these enzymes and defines t he active site cavity.