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 A resolution, reveals the active-site geometry and defines multiple possible target sites for drug design against a human cancer-producing virus. The catalytic triad of KSHV Pr, (Ser114, His46, and His157) and transition-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 of serine proteases. As in all herpesviral proteases, the enzyme is active only as a weakly associated dimer (K(d) approximately 2 microM), and inactive as a monomer. Therefore, both the active site and dimer interface are potential targets 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 destabilizing element contributing to the tuned micromolar dissociation of herpesviral protease dimers.
Reiling
K K
KK
Departments of Biochemistry & Biophysics and Pharmaceutical Chemistry, and Graduate Group in Biophysics, University of California in San Francisco, San Francisco, California 94143, USA.
Pray
T R
TR
Craik
C S
CS
Stroud
R M
RM
D000595:Amino Acid Sequence; D000838:Anions; D001665:Binding Sites; D002384:Catalysis; D020134:Catalytic Domain; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D019281:Dimerization; D004789:Enzyme Activation; D019288:Herpesvirus 8, Human / Q000201:enzymology*; D006801:Humans; D008969:Molecular Sequence Data; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012697:Serine Endopeptidases / Q000737:chemistry*; D013379:Substrate Specificity
D000838:Anions; D012697:Serine Endopeptidases; C107889:human herpesvirus 8 protease