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

Nature Structural & Molecular Biology volume 13, pages 372–373 (2006)Cite this article

Abstract

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.

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Figure 1: Structures of NS2B–NS3pro in the absence and presence of an inhibitor.
Figure 2: Stereo view of the substrate-binding region of WNV NS2B–NS3pro, colored as in Figure 1.

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Acknowledgements

We thank W. Kabsch for advice, E. Pohl for support at the beamline and J. Lescar, J.P. Priestle and J. Eder for critical reading.

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Author notes

  1. Paul Erbel and Nikolaus Schiering: These authors contributed equally to this work.

Authors and Affiliations

  1. Novartis Institutes for Biomedical Research, Protease Platform, Basel, 4002, Switzerland

    Paul Erbel, Nikolaus Schiering, Allan D'Arcy, Martin Renatus & Ulrich Hommel

  2. Novartis Institutes for Biomedical Research, Discovery Technologies, Basel, 4002, Switzerland

    Markus Kroemer

  3. Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore, 138670, Singapore

    Siew Pheng Lim, Zheng Yin, Thomas H Keller & Subhash G Vasudevan

Authors
  1. Paul Erbel
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  2. Nikolaus Schiering
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  3. Allan D'Arcy
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  4. Martin Renatus
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  5. Markus Kroemer
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  6. Siew Pheng Lim
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  7. Zheng Yin
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  8. Thomas H Keller
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  9. Subhash G Vasudevan
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  10. Ulrich Hommel
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Corresponding author

Correspondence to Ulrich Hommel.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Genome organization of WNV and DEN polyprotein (PDF 109 kb)

Supplementary Fig. 2

Sequence alignment (PDF 204 kb)

Supplementary Fig. 3

Stereo view of experimental electron density maps (PDF 2021 kb)

Supplementary Fig. 4

Inhibitor binding monitored by NMR (PDF 1059 kb)

Supplementary Table 1

Data collection and refinement statistics (PDF 79 kb)

Supplementary Table 2

Activities of WNV NS3 protease inhibitors (PDF 103 kb)

Supplementary Methods (PDF 128 kb)

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Erbel, P., Schiering, N., D'Arcy, A. et al. Structural basis for the activation of flaviviral NS3 proteases from dengue and West Nile virus. Nat Struct Mol Biol 13, 372–373 (2006). https://doi.org/10.1038/nsmb1073

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