Structural basis for the activation of flaviviral NS3 proteases from dengue and West Nile virus

The replication of flaviviruses requires the correct processing of their polyprotein by the viral NS3 protease (NS3pro). Essential for the activation of NS3pro is a 47-residue region of NS2B. Here we report the crystal structures of a dengue NS2B–NS3pro complex and a West Nile virus NS2B–NS3pro complex with a substrate-based inhibitor. These structures identify key residues for NS3pro substrate recognition and clarify the mechanism of NS3pro activation.

[1]  Martin J. Stoermer,et al.  Activity of Recombinant Dengue 2 Virus NS3 Protease in the Presence of a Truncated NS2B Co-factor, Small Peptide Substrates, and Inhibitors* , 2001, The Journal of Biological Chemistry.

[2]  R. Yusof,et al.  Purified NS2B/NS3 Serine Protease of Dengue Virus Type 2 Exhibits Cofactor NS2B Dependence for Cleavage of Substrates with Dibasic Amino Acids in Vitro* , 2000, The Journal of Biological Chemistry.

[3]  R. Padmanabhan,et al.  Dengue Virus NS3 Serine Protease , 1999, The Journal of Biological Chemistry.

[4]  L. DeLucas,et al.  Crystal structure of Dengue virus NS3 protease in complex with a Bowman-Birk inhibitor: implications for flaviviral polyprotein processing and drug design. , 2000, Journal of molecular biology.

[5]  D. Fairlie,et al.  Homology model of the dengue 2 virus NS3 protease: putative interactions with both substrate and NS2B cofactor. , 1999, The Journal of general virology.

[6]  S. Vasudevan,et al.  Peptide inhibitors of dengue virus NS3 protease. Part 2: SAR study of tetrapeptide aldehyde inhibitors. , 2006, Bioorganic & medicinal chemistry letters.

[7]  Martin J. Stoermer,et al.  Site-directed Mutagenesis and Kinetic Studies of the West Nile Virus NS3 Protease Identify Key Enzyme-Substrate Interactions* , 2005, Journal of Biological Chemistry.

[8]  Steven R. LaPlante,et al.  An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus , 2003, Nature.

[9]  A. Urbani,et al.  Activity of purified hepatitis C virus protease NS3 on peptide substrates , 1996, Journal of virology.

[10]  H. Parge,et al.  The Crystal Structure of Hepatitis C Virus NS3 Proteinase Reveals a Trypsin-like Fold and a Structural Zinc Binding Site , 1996, Cell.

[11]  Martin J. Stoermer,et al.  Enzymatic Characterization and Homology Model of a Catalytically Active Recombinant West Nile Virus NS3 Protease* , 2004, Journal of Biological Chemistry.

[12]  M. Murcko,et al.  Crystal Structure of the Hepatitis C Virus NS3 Protease Domain Complexed with a Synthetic NS4A Cofactor Peptide , 1996, Cell.

[13]  C. Rice,et al.  Flavivirus genome organization, expression, and replication. , 1990, Annual review of microbiology.