Functional consequences of the Kaposi's sarcoma-associated herpesvirus protease structure: Regulation of activity and dimerization by conserved structural elements

The structure of Kaposi's sarcoma-associated herpesvirus protease (KSHV Pr) , at 2.2 Angstrom resolution, reveals the active-site geometry and defines multiple possible target sites fur drug design against a human cancer-produ cing virus. The catalytic triad of KSWV Pr, (Ser114, His46, and His157) and Transition-state stabilization site are arranged as in other structurally characterized herpesviral proteases. The distal histidine-histidine hydroge n bond is solvent accessible, unlike the situation in other classes of seri ne proteases. As in all herpesviral proteases, the enzyme is active only as a weakly associated dimer (K-d approximate to 2 muM), and inactive as a mo nomer. Therefore, both the active site and dimer interface are potential ta rgets for antiviral drug design. The dimer interface in KSHV Pr is compared with the interface of other herpesviral proteases. Two conserved arginines (Arg209), one from each monomer, are buried within the same region of the dimer interface, We propose that this conserved arginine may provide a dest abilizing element contributing to the tuned micromolar dissociation of herp esviral protease dimers.