| Abstract
| - The structure of Kaposi's sarcoma-associated herpesvirus protease (KSHV Pr), at 2.2 Åresolution, reveals the active-site geometry and defines multiple possible target sites for drug design againsta human cancer-producing virus. The catalytic triad of KSHV Pr, (Ser114, His46, and His157) andtransition-state stabilization site are arranged as in other structurally characterized herpesviral proteases.The distal histidine−histidine hydrogen bond is solvent accessible, unlike the situation in other classes ofserine proteases. As in all herpesviral proteases, the enzyme is active only as a weakly associated dimer(Kd ≈ 2 μM), and inactive as a monomer. Therefore, both the active site and dimer interface are potentialtargets for antiviral drug design. The dimer interface in KSHV Pr is compared with the interface of otherherpesviral proteases. Two conserved arginines (Arg209), one from each monomer, are buried within thesame region of the dimer interface. We propose that this conserved arginine may provide a destabilizingelement contributing to the tuned micromolar dissociation of herpesviral protease dimers.
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