title: Mechanism of 150-cavity formation in influenza neuraminidase.
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.
authors.affiliation: Department of Pharmaceutical Sciences, Computer Science and Chemistry, University of California, Irvine, California 92697, USA. ramaro@uci.edu
authors.forename: Rommie E
authors.initials: RE
authors.lastname: Amaro
authors.forename: Robert V
authors.initials: RV
authors.lastname: Swift
authors.forename: Lane
authors.initials: L
authors.lastname: Votapka
authors.forename: Wilfred W
authors.initials: WW
authors.lastname: Li
authors.forename: Ross C
authors.initials: RC
authors.lastname: Walker
authors.forename: Robin M
authors.initials: RM
authors.lastname: Bush
mesh_terms: D001499:Bayes Theorem; D020134:Catalytic Domain / Q000235:genetics*; D019295:Computational Biology; D053118:Influenza A Virus, H1N1 Subtype / Q000201:enzymology*; D008957:Models, Genetic; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009439:Neuraminidase / Q000737:chemistry*; D010802:Phylogeny; D011487:Protein Conformation; D013045:Species Specificity
chemical_list: D009439:Neuraminidase