%0 Journal Article %A Brinkworth, Ross I. %A Fairlie, David P. %A Leung, Donmienne %A Young, Paul R. %T Homology model of the dengue 2 virus NS3 protease: putative interactions with both substrate and NS2B cofactor %D 1999 %J Journal of General Virology, %V 80 %N 5 %P 1167-1177 %@ 1465-2099 %R https://doi.org/10.1099/0022-1317-80-5-1167 %I Microbiology Society, %X The crystal structure coordinates of the hepatitis C virus NS3 protease (HCVpro) were used to develop an homology model of the dengue 2 virus NS3 protease (DEN2pro). The amino acid sequence of DEN2pro accommodates the same alpha-helices, beta-sheets and protein-binding domains as its HCVpro counterpart, but the model predicts a number of significant differences for DEN2pro and its interactions with substrates and cofactor. Whereas HCVpro contains a Zn2+-binding site, there is no equivalent metal-binding motif in DEN2pro. It is possible that the structural role played by the zinc ion may be provided by a salt bridge between Glu93 and Lys145. The two-component viral protease comprises NS3 and a virus-encoded cofactor, NS4A for HCV and NS2B for DEN2. Previous studies have identified a central 40 amino acid cofactor domain of the dengue virus NS2B that is required for protease activity. Modelling of the putative interactions between DEN2pro and its cofactor suggests that a 12 amino acid hydrophobic region within this sequence (70GSSPILSITISE81) may associate directly with NS3. Modelling also suggests that the substrate binds in an extended conformation to the solvent-exposed surface of the protease, with a P1-binding site that is significantly different from its HCV counterpart. The model described in this study not only reveals unique features of the flavivirus protease but also provides a structural basis for both cofactor and substrate binding that should prove useful in the early design and development of inhibitors. %U https://www.microbiologyresearch.org/content/journal/jgv/10.1099/0022-1317-80-5-1167