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Nat Commun. 2011 Jul 12;2:388. doi: 10.1038/ncomms1390.

Mechanism of 150-cavity formation in influenza neuraminidase.

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1
Department of Pharmaceutical Sciences, Computer Science and Chemistry, University of California, Irvine, California 92697, USA. ramaro@uci.edu

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) neuraminidase 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.

PMID:
21750542
PMCID:
PMC3144582
DOI:
10.1038/ncomms1390
[Indexed for MEDLINE]
Free PMC Article
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