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Document Figure 6 Stereo image of a ball-and-stick model of sialic acid bound to the active site of Tern/N9 neuraminidase. The hydrogen-bond interactions with conserved residues are shown as dotted lines. Nitrogen atoms are shaded black, oxygen atoms are shaded dark gray, and carbon atom are shaded light gray. Page 470 a pocket of totally conserved (over all animal subtypes) residues [65]. In this way the enzyme active-site pocket is surrounded by highly variable surface residues that prevent immune recognition of the active site by antibody molecules [25]. The x-ray diffraction studies of neuraminidase—antibody complexes have shown that the footprint of an antibody in the complex is larger than the exposed surface of the conserved region of the active site [67–69]. These structural results indicate that antibodies are unable to exert mutational pressure on the conserved active site because they cannot bind there without engaging strain-variable residues as part of the binding surface. However, as antibodies bind to strain-variable elements of the structure, the virus can overcome host immune pressure by point mutations of the residues that do not have a catalytic or structural role [70,48] but are able to disrupt the antigen—antibody binding interface. The rapid emergence of these escape mutants explains the failure in producing a universal vaccine for influenza. E. The Enzyme Active Site The structures of N-acetyl neuraminic acid (sialic acid Neu5Ac) and the 2-deoxy-2,3-dehydro-N-acetyl neuraminic acid (Neu5Ac2en) inhibitor complexed with N2 neuraminidase [66] revealed the nature of the interactions of the http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_470.html [4/9/2004 12:22:22 AM]
Document Page 471 molecules in the active-site pocket (Figure 6). Sialic acid binds in the active site in the α-anomer and, in a distorted half-chair conformation, through the same face as used in its interaction with hemagglutinin [71]. The carboxylate group of the sugar interacts with three guanidinium groups of argine residues 118, 292, and 371 and has an equatorial conformation with respect to the sugar ring (this group, axial toward the floor in the undistorted structure, is probably held equatorial by interactions with these arginine residues). The NH group of the 5-N-acetyl side chain interacts with the floor of the active-site cavity via a bound water molecule. The oxygen of the 5-N-acetyl side chain is hydrogen bonded to the N ε of Arg 152, while the methyl group lies in a hydrophobic pocket near Ile222 and Trp178. The last two hydroxyl groups of the 6-glycerol side chain are hydrogen bonded to carboxylate oxygens of Glu276 and the 4hydroxyl is directed to a carboxylate oxygen of Glu119. The glycosidic oxygen O2 interacts with a carboxylate oxygen of Asp151. Similar binding of sialic acid in the active site was observed in type B virus [50]. Comparison of active sites of N2, N9, and type B neuraminidase [72] show there are no significant differences between active-site orientations, except for some minor displacements of Arg224 and Glu276, where the major interactions with the 6-glycerol group of sialic acid occur. However there are differences in the water structure in the active sites of the different subtypes. The Gly405 residue (in N2 and N9) is replaced by a tryptophan in type B, which displaces four water molecules that lie in a solvent pocket bounded by arginines at residues 371 and 118. The Val240 residue (in N2 and N9) is replaced by a methionine in type B, which displaces two water molecules that form a channel under Arg 224, decreasing the flexibility of the active site of type B in this region. These waters are not displaced in the sialic acid/neuraminidase complex in N9 and N2 and would alter the hydrogen-bonding pattern of the complexes when compared to type B. Comparison of the active sites of influenza neuraminidases and bacterial sialidases [51,52] indicates that there is considerable conservation of the catalytic site at the carboxylate-binding end. The residues Asp151, Arg118, Glu277, Arg292, Val or Ile349, Arg371, Tyr406, and Glu425 are conserved over all known viral and bacterial strains. The arginyl residues 118, 292, and 371 position the 2-carboxylate group and the Val(or Ile)349, Glu425, and Glu277 are important in positioning the triarginyl cluster. The residues Asp151 and Tyr406 are presumably important in bond cleavage, but the precise mechanism is still unclear. These eight residues (Figure 7) are thus most likely to be conserved in all neuraminidases. Differences between viral, bacterial, and mammalian neuraminidase structures may correspond with the different role these enzymes have in vivo. These differences are likely to be in the interactions of the 6glycerol, 5-N-acetyl, and 4-OH groups of silaic acid. In the influenza virus, the turnover rate must be balanced against the requirement to maintain http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_471.html [4/9/2004 12:22:26 AM]
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Document [Protease targets] serinyl
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