2ijo

From Proteopedia

Revision as of 13:16, 23 January 2008

Crystal Structure of the West Nile virus NS2B-NS3 protease complexed with bovine pancreatic trypsin inhibitor

Overview

Pathogenic members of the flavivirus family, including West Nile Virus, (WNV) and Dengue Virus (DV), are growing global threats for which there, are no specific treatments. The two-component flaviviral enzyme NS2B-NS3, cleaves the viral polyprotein precursor within the host cell, a process, that is required for viral replication. Here, we report the crystal, structure of WNV NS2B-NS3pro both in a substrate-free form and in complex, with the trypsin inhibitor aprotinin/BPTI. We show that aprotinin binds in, a substrate-mimetic fashion in which the productive conformation of the, protease is fully formed, providing evidence for an "induced fit", mechanism of catalysis and allowing us to rationalize the distinct, substrate specificities of WNV and DV proteases. We also show that the, NS2B cofactor of WNV can adopt two very distinct conformations and that, this is likely to be a general feature of flaviviral proteases, providing, further opportunities for regulation. Finally, by comparing the flaviviral, proteases with the more distantly related Hepatitis C virus, we provide, insights into the evolution of the Flaviviridae fold. Our work should, expedite the design of protease inhibitors to treat a range of flaviviral, infections.

About this Structure

2IJO is a Protein complex structure of sequences from Bos taurus and West nile virus. Active as Flavivirin, with EC number 3.4.21.91 Full crystallographic information is available from OCA.

Reference

Structural evidence for regulation and specificity of flaviviral proteases and evolution of the Flaviviridae fold., Aleshin AE, Shiryaev SA, Strongin AY, Liddington RC, Protein Sci. 2007 May;16(5):795-806. Epub 2007 Mar 30. PMID:17400917

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