2ggv
From Proteopedia
(New page: 200px<br /><applet load="2ggv" size="350" color="white" frame="true" align="right" spinBox="true" caption="2ggv, resolution 1.800Å" /> '''Crystal structure o...) |
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==Overview== | ==Overview== | ||
| - | Pathogenic members of the flavivirus family, including West Nile Virus | + | 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== | ==About this Structure== | ||
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[[Category: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: West nile virus]] | [[Category: West nile virus]] | ||
| - | [[Category: Aleshin, A | + | [[Category: Aleshin, A E.]] |
| - | [[Category: Liddington, R | + | [[Category: Liddington, R C.]] |
| - | [[Category: Shiryaev, S | + | [[Category: Shiryaev, S A.]] |
| - | [[Category: Strongin, A | + | [[Category: Strongin, A Y.]] |
[[Category: beta barrel]] | [[Category: beta barrel]] | ||
[[Category: flavivirus]] | [[Category: flavivirus]] | ||
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[[Category: viral protease]] | [[Category: viral protease]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:31:39 2008'' |
Revision as of 15:31, 21 February 2008
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Crystal structure of the West Nile virus NS2B-NS3 protease, His51Ala mutant
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
2GGV is a Protein complex structure of sequences from West nile virus. 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
Page seeded by OCA on Thu Feb 21 17:31:39 2008
