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388 a.a.
107 a.a.
116 a.a.
Key reference
DOI no: 10.1016/j.jmb.2005.11.061 J Mol Biol 356:651-663 (2006) PubMed id: 16384583
An Epidemiologically Significant Epitope of a 1998 Human Influenza Virus Neuraminidase Forms a Highly Hydrated Interface in the NA-Antibody Complex. L.Venkatramani, E.Bochkareva, J.T.Lee, U.Gulati, W.Graeme Laver, A.Bochkarev, G.M.Air. ABSTRACT
The crystal structure of the complex between neuraminidase (NA) of influenza virus A/Memphis/31/98 (H3N2) and Fab of monoclonal antibody Mem5 has been determined at 2.1A resolution and shows a novel pattern of interactions compared to other NA-Fab structures. The interface buries a large area of 2400A(2) and the surfaces have high complementarity. However, the interface is also highly hydrated. There are 33 water molecules in the interface >/=95% buried from bulk solvent, but only 13 of these are isolated from other water molecules. The rest are involved in an intricate network of water-mediated hydrogen bonds throughout the interface, stabilizing the complex. Glu199 on NA, the most critical side-chain to the interaction as previously determined by escape mutant analysis and site-directed mutation, is located in a non-aqueous island. Glu199 and three other residues that contribute the major part of the antigen buried surface of the complex have mutated in human influenza viruses isolated after 1998, confirming that Mem5 identifies an epidemiologically important antigenic site. We conclude that antibody selection of NA variants is a significant component of recent antigenic drift in human H3N2 influenza viruses, supporting the idea that influenza vaccines should contain NA in addition to hemagglutinin.
Selected figure(s)
Figure 1.
Figure 1. Crystal structures of NA-Fab complexes showing the different binding site in Mem/98 NA compared to N9 NA. (a)-(c). The NA (brown) is shown in approximately the same orientation in each panel. The antibody heavy chain is in blue, the light chain is in mauve. N-linked carbohydrates are in green; the long carbohydrate chain is attached to Asn200. The view is looking parallel with the viral membrane, with the Pronase cleavage site at the bottom. The stalk would continue down the page to the viral membrane. (a) Stereo view of the Mem/98 N2 NA-Mem5 Fab complex. Electron density was not continuous for the constant domains of Mem5 Fab and only part of those are included. A sulfate ion (red spheres) marks the active site. (b) The N9 NA-NC41 Fab complex (PDB 1NCA). Only the Fv domain of the antibody is shown. (c) N9 NA-NC10 Fab complex (PDB 1NMB). Contacts include the carbohydrate chain attached to Asn200 of the adjacent subunit, so that chain is included in the asymmetric unit. (d) Looking down on to the top surface of the N9 NA tetramer (green) with four Fvs of NC10 bound. (e) The Mem/98 NA tetramer with four Fvs of Mem5 bound. The images were prepared using PyMol (DeLano Scientific).Figure 4.
Figure 4. Water molecules form an intricate network of hydrogen-bonded water molecules across the interface and water-mediated hydrogen bonds between the NA and Fab. (a) The water network encircles Glu199. Broken lines are water-water hydrogen bonds. (b) Schematic of the water interactions in the interface. The water molecules are identified in magenta, NA residues are green, antibody H chain residues are dark blue and L chain residues are light blue. H-bonds are black lines. Direct contacts between protein residues are shown by broken red lines to give a sense of the spatial relationships.The above figures are reprinted by permission from Elsevier: J Mol Biol (2006, 356, 651-663) copyright 2006. Figures were selected by an automated process.
Literature references that cite this PDB file's key reference
PubMed id Reference
19564683 F.Ni, B.K.Poon, Q.Wang, and J.Ma (2009).
Application of normal-mode refinement to X-ray crystal structures at the lower resolution limit.Acta Crystallogr D Biol Crystallogr, 65, 633-643.
19457254 S.Maurer-Stroh, J.Ma, R.T.Lee, F.L.Sirota, and F.Eisenhaber (2009).
Mapping the sequence mutations of the 2009 H1N1 influenza A virus neuraminidase relative to drug and antibody binding sites.Biol Direct, 4, 18; discussion 18.
17313688 J.E.Beaver, P.E.Bourne, and J.V.Ponomarenko (2007).
EpitopeViewer: a Java application for the visualization and analysis of immune epitopes in the Immune Epitope Database and Analysis Resource (IEDB).Immunome Res, 3, 3. The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.
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