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Mechanism of 150-cavity formation in influenza neuraminidase

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Listed:
  • Rommie E. Amaro

    (Computer Science and Chemistry, University of California)

  • Robert V. Swift

    (Computer Science and Chemistry, University of California)

  • Lane Votapka

    (Computer Science and Chemistry, University of California)

  • Wilfred W. Li

    (National Biomedical Computation Resource, University of California
    San Diego)

  • Ross C. Walker

    (San Diego Supercomputer Center, University of California
    San Diego)

  • Robin M. Bush

    (University of California)

Abstract

The recently discovered 150-cavity in the active site of group-1 influenza A neuraminidase (NA) proteins provides a target for rational structure-based drug development to counter the increasing frequency of antiviral resistance in influenza. Surprisingly, the 2009 H1N1 pandemic virus (09N1) neuramidase was crystalized without the 150-cavity characteristic of group-1 NAs. Here we demonstrate, through a total sum of 1.6 μs of biophysical simulations, that 09N1 NA exists in solution preferentially with an open 150-cavity. Comparison with simulations using avian N1, human N2 and 09N1 with a I149V mutation and an extensive bioinformatics analysis suggests that the conservation of a key salt bridge is crucial in the stabilization of the 150-cavity across both subtypes. This result provides an atomic-level structural understanding of the recent finding that antiviral compounds designed to take advantage of contacts in the 150-cavity can inactivate both 2009 H1N1 pandemic and avian H5N1 viruses.

Suggested Citation

  • Rommie E. Amaro & Robert V. Swift & Lane Votapka & Wilfred W. Li & Ross C. Walker & Robin M. Bush, 2011. "Mechanism of 150-cavity formation in influenza neuraminidase," Nature Communications, Nature, vol. 2(1), pages 1-7, September.
    • Handle: RePEc:nat:natcom:v:2:y:2011:i:1:d:10.1038_ncomms1390
    DOI: 10.1038/ncomms1390
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