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. 2011 Jul 12:2:388.
doi: 10.1038/ncomms1390.

Mechanism of 150-cavity formation in influenza neuraminidase

Rommie E Amaro  1 , Robert V Swift, Lane Votapka, Wilfred W Li, Ross C Walker, Robin M Bush
Affiliations
Free PMC article

Mechanism of 150-cavity formation in influenza neuraminidase

Rommie E Amaro et al. Nat Commun. .
Free PMC article

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.

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Figures

Figure 1
Figure 1. Solvent accessible surface area of NA-binding site.
The solvent accessible surface area of the NA-binding site is shown, as computed by the MSMS program, for the X-ray structure, and top three most dominant central member cluster structures (population percentages indicated in white text for each cluster), shown for A/Tokyo/3/67 (N2), A/Vietnam/1203/04 (VN04N1), A/California/04/2009 (09N1) and the 09N1_I149V mutant strain. The open 150-cavity, where present, is outlined with a dotted circle.
Figure 2
Figure 2. Time series analysis of 150-cavity volume and width for a particular monomer in each of the simulated systems.
On the left-side y axis, the volume of the 150-cavity is computed over the course of simulation. The distance between alpha-carbon of residue 431 (PRO in a, b, d; LYS in c) and the closest side-chain carbon of residue 149 (Val149 panels b, c, d; ILE in a) is computed and shown in red and the right-side y axis. The black and red dotted lines correspond to the open crystal structure (2HTY) volume and distance, respectively; whereas the black dashed and red solid lines correspond to the closed crystal structure (2HU4) volume and distance, respectively. The systems shown are A/Tokyo/3/67 (N2), A/Vietnam/1203/04 (VN04N1), A/California/04/2009 (09N1) and the 09N1_I149V mutant strain.
Figure 3
Figure 3. Structural variation in N1 and N2 clinical isolates.
(a) The 150- and 430-loop structures are shown for 09N1 crystal structure (purple), 09N1 second most dominant molecular dynamics (MD) cluster representative structure (green backbone) and VN04N1 crystal structure (orange), indicating that the pandemic N1 adopts an open 150-loop conformation. Gly147, Ile149, Lys150 and Pro431 are shown in stick representation. (b) N2 150- and 430-loops from crystal and most dominant cluster representative structures are shown in blue, and open VN04N1 crystal structure are shown in orange. The D147-H150 salt bridge spontaneously ruptures in chain C of N2, extending its initial contact from 2.8 Å in crystal structure to 11.8 Å in the most dominant MD-generated cluster structure, revealing a wide-open 150-cavity.
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References

    1. Russell R. J. et al.. The structure of H5N1 avian influenza neuraminidase suggests new opportunities for drug design. Nature 443, 45–49 (2006). - PubMed
    1. von Itzstein M. The war against influenza: discovery and development of sialidase inhibitors. Nat. Rev. Drug Discov. 6, 967–974 (2007). - PubMed
    1. Rudrawar S. et al.. Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase. Nat. Commun. 1, 113 (2011). - PMC - PubMed
    1. Dharan N. J. et al.. Infections with oseltamivir-resistant influenza A(H1N1) virus in the United States. JAMA 301, 1034–1041 (2009). - PubMed
    1. Li Q. et al.. The 2009 pandemic H1N1 neuraminidase N1 lacks the 150-cavity in its active site. Nat. Struct. Mol. Biol. 17, 1266–1268 (2010). - PubMed

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