Mechanism of 150-cavity formation in influenza neuraminidase

Rommie E. Amaro (), Robert V. Swift, Lane Votapka, Wilfred W. Li, Ross C. Walker and Robin M. Bush
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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
Ross C. Walker: San Diego Supercomputer Center, University of California
Robin M. Bush: University of California

Nature Communications, 2011, vol. 2, issue 1, 1-7

Abstract: 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.

Date: 2011
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DOI: 10.1038/ncomms1390

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