JVI Accepts, published online ahead of print on 20 August 2008

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J. Virol. doi:10.1128/JVI.00959-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Structural characterization of the 1918 influenza H1N1 neuraminidase

Xiaojin Xu, Xueyong Zhu, Raymond A. Dwek, James Stevens, and Ian A. Wilson^*

Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA; Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA; Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK

^* To whom correspondence should be addressed. Email: wilson{at}scripps.edu.

Influenza virus neuraminidase (NA) plays a crucial role in facilitating the spread of newly synthesized virus in the host and is an important target for controlling disease progression. The NA crystal structure from 1918 ‘Spanish flu’ (A/Brevig Mission/1/18 H1N1), and its complex with zanamivir (Relenza®), at 1.65 Å and 1.45 Å resolutions, respectively, corroborated the successful expression of correctly folded NA tetramers in a baculovirus expression system. Compared to N2 and N9, an additional cavity adjacent to the substrate-binding site is observed in N1 NAs, including H5N1, that arises from an open conformation of the 150-loop (Gly147-Asp151), and appears to be conserved among Group 1 NAs (N1, N4, N5 and N8). This cavity closes upon zanamivir binding. Three calcium sites were identified, including a novel site that may be conserved in N1 and N4. Thus, these high resolution structures, combined with our recombinant expression system, provide new opportunities to augment the limited arsenal of therapeutics against influenza.

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