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      Structure-based mutagenesis identifies important novel determinants of the NS2B cofactor of the West Nile virus two-component NS2B-NS3 proteinase.

      The Journal of General Virology

      genetics, Amino Acid Sequence, enzymology, West Nile virus, metabolism, chemistry, Viral Nonstructural Proteins, Structure-Activity Relationship, Serine Endopeptidases, Sequence Alignment, RNA Helicases, Mutagenesis, Site-Directed, Molecular Sequence Data, Models, Molecular, Gene Expression Regulation, Viral, Crystallization, Circular Dichroism

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          Abstract

          West Nile virus (WNV) is an emerging mosquito-borne flavivirus that causes neuronal damage in the absence of treatment. In many flaviviruses, including WNV, the NS2B cofactor promotes the productive folding and the functional activity of the two-component NS3 (pro)teinase. Based on an analysis of the NS2B-NS3pro structure, we hypothesized that the G(22) residue and the negatively charged patch D(32)DD(34) of NS2B were part of an important configuration required for NS2B-NS3pro activity. Our experimental data confirmed that G(22) and D(32)DD(34) substitution for S and AAA, respectively, inactivated NS2B-NS3pro. An additional D42G mutant, which we designed as a control, had no dramatic effect on either the catalytic activity or self-proteolysis of NS2B-NS3pro. Because of the significant level of homology in flaviviral NS2B-NS3pro, our results will be useful for the development of specific allosteric inhibitors designed to interfere with the productive interactions of NS2B with NS3pro.

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          Journal
          18272753
          10.1099/vir.0.83359-0

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