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Review
. 2010 Sep 10;285(37):28403-9.
doi: 10.1074/jbc.R110.129809. Epub 2010 Jun 10.

Influenza Hemagglutinin and Neuraminidase Membrane Glycoproteins

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Free PMC article
Review

Influenza Hemagglutinin and Neuraminidase Membrane Glycoproteins

Steven J Gamblin et al. J Biol Chem. .
Free PMC article

Abstract

Considerable progress has been made toward understanding the structural basis of the interaction of the two major surface glycoproteins of influenza A virus with their common ligand/substrate: carbohydrate chains terminating in sialic acid. The specificity of virus attachment to target cells is mediated by hemagglutinin, which acquires characteristic changes in its receptor-binding site to switch its host from avian species to humans. Anti-influenza drugs mimic the natural sialic acid substrate of the virus neuraminidase enzyme but utilize the much tighter binding of the drugs for efficacy. Resistance to one of the two main antiviral drugs is differentially acquired by the two distinct subsets of neuraminidase as a consequence of structural differences in the enzyme active site between the two phylogenetic groups.

Figures

FIGURE 1.
FIGURE 1.
Crystal structures and phylogenetic organization of pandemic HAs. The upper and middle panels show two orthogonal views of the H1, H2, and H3 HAs in ribbon representation. Two of the monomers from each trimer are in gold and silver, whereas the subunits that make up the third monomer are colored as follows: blue, receptor binding; yellow, vestigial esterase; and magenta and red, fusion subdomains (25). The lower panel shows a phylogenetic tree containing the 16 subtypes of HA that fall into two distinct groups. As well as local variations in structure, there are significant differences in rigid body orientation of subdomains between HAs in the groups. The arrow indicates rotation of the membrane-distal subdomains of group 2 H3 HA relative to those of group 1 H1 and H2 HAs.
FIGURE 2.
FIGURE 2.
Crystal structures of complexes between HA and receptor analogs. The upper panels show sialic acid linked to Gal-2 and GlcNAc-3 from the α2,6-linked human receptor analog LSTc (38) (left; carbons colored blue) and the α2,3-linked avian receptor analog LSTa (right; carbons colored yellow). The black arrows indicate the glycosidic oxygen in both cases. The middle and lower panels show overlaps of the receptor-binding domains of HAs from different species and subtypes in complex with the human receptor (left) and avian receptor (right). The three secondary structure elements of the site, the 130- and 220-loops and the 190-helix, are labeled. The HA and carbon atoms of the ligand are colored blue for H1, yellow for H2, gray for H3, and salmon for H5.
FIGURE 3.
FIGURE 3.
Phylogenetic organization and crystal structures of NA. The upper left panel shows a phylogenetic tree of the nine NA subtypes of influenza A together with NA from influenza B. The influenza A NAs fall into two distinct groups. The lower left panel shows a ribbon representation of an NA tetramer viewed along the 4-fold axis. Three of the monomers are colored green, whereas for the fourth monomer, each of the six blades that make up the structure is separately colored (80). The right panel shows a detailed view of the NA active site in an overlap between a group 1 structure (in green) and a group 2 structure (in yellow), with some key side chains shown in ball-and-stick representation. Sialic acid has been docked into the overlapped structures.
FIGURE 4.
FIGURE 4.
Inhibitor binding to the active site of NA. The upper panel shows a C-α trace for wild-type N1 (in yellow), with bound oseltamivir and selected side chains colored yellow for the wild-type complex and green for the mutant complex. Thr-252 of group 2 NA is light blue. In the lower panel, the structures of sialic acid, zanamivir, and oseltamivir are shown in blue, gray, and yellow, respectively, with selected carbon atoms associated with the hydrophobic moiety at C-6 of oseltamivir numbered.

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