Special features of the 2009 pandemic swine-origin influenza A H1N1 hemagglutinin and neuraminidase

Vavricka, Christopher J.; Liu, Yue; Li, Qing; Shi, Yi; Wu, Yan; Sun, Yeping; Qi, Jianxun; Gao, George F.

doi:10.1007/s11434-011-4517-9

Cited by 15 publications

(12 citation statements)

References 49 publications

(58 reference statements)

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“…These interactions may limit either the movement on inhibitor binding, as shown in typical group 1 NA crystal structures (17,19,20), or the variant conformations in solution, as seen in the molecular dynamics simulations with several group 2 NAs (29,30). In addition, there is still the possibility that the 150-loop of N10 might not be involved in catalysis, whereas the flexible 150-loop in canonical influenza NA might act as an important switch in the catalytic cycle (37).…”

Section: Discussionmentioning

confidence: 99%

Structural and functional characterization of neuraminidase-like molecule N10 derived from bat influenza A virus

Sun

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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108

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The recent discovery of the unique genome of influenza virus H17N10 in bats raises considerable doubt about the origin and evolution of influenza A viruses. It also identifies a neuraminidase (NA)-like protein, N10, that is highly divergent from the nine other well-established serotypes of influenza A NA (N1–N9). The structural elucidation and functional characterization of influenza NAs have illustrated the complexity of NA structures, thus raising a key question as to whether N10 has a special structure and function. Here the crystal structure of N10, derived from influenza virus A/little yellow-shouldered bat/Guatemala/153/2009 (H17N10), was solved at a resolution of 2.20 Å. Overall, the structure of N10 was found to be similar to that of the other known influenza NA structures. In vitro enzymatic assays demonstrated that N10 lacks canonical NA activity. A detailed structural analysis revealed dramatic alterations of the conserved active site residues that are unfavorable for the binding and cleavage of terminally linked sialic acid receptors. Furthermore, an unusual 150-loop (residues 147–152) was observed to participate in the intermolecular polar interactions between adjacent N10 molecules of the N10 tetramer. Our study of influenza N10 provides insight into the structure and function of the sialidase superfamily and sheds light on the molecular mechanism of bat influenza virus infection.

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Section: Discussionmentioning

confidence: 99%

Structural and functional characterization of neuraminidase-like molecule N10 derived from bat influenza A virus

Sun

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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108

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“…Two major glycoproteins, hemagglutinin (HA) and NA, as well as the M2 ion channel, are on the surface of the virions and are therefore highly accessible targets for drug development 6,7 . Of these three transmembrane proteins, only NA is known to function as an enzyme and is therefore an ideal target for the design of competitive inhibitors that can mimic catalytic transition-state intermediates 8 .…”

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confidence: 99%

Influenza neuraminidase operates via a nucleophilic mechanism and can be targeted by covalent inhibitors

et al. 2013

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“…By hydrolyzing the bond of terminally linked sialic acid in the influenza virus receptor, NA facilitates the release and migration of virions (7). The nine serotypes of NA from influenza A virus (N1 to N9) have been classified into two groups based upon phylogenetic analysis (group 1 includes N1, N4, N5, and N8; group 2 includes N2, N3, N6, N7, and N9) before the divergent NA-like N10 was identified in bats (8)(9)(10).…”

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confidence: 99%

“…Crystal structures of seven out of nine of the influenza A virus serotypes have been solved to date (11), leaving N3 and N7 as the last two structure-unknown influenza virus NA serotypes. With the exception of the N1 from the 2009 H1N1 pandemic, all group 1 NAs have contained a 150-cavity adjacent to their active site, formed by the opening of the 150-loop (residues 147 to 150), and all group 2 NA structures have lacked this cavity (7). High-resolution NA structures have led to the successful design and worldwide approval of two NA drugs: oseltamivir and zanamivir (12,13).…”

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Functional and Structural Analysis of Influenza Virus Neuraminidase N3 Offers Further Insight into the Mechanisms of Oseltamivir Resistance

et al. 2013

J Virol

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The influenza virus neuraminidase H274Y substitution is a highly prevalent amino acid substitution associated with resistance to the most heavily used influenza drug, oseltamivir. Previous structural studies suggest that the group specific 252 residue (Y252 in group 1 and T252 in group 2) might be a key factor underlying H274Y resistance. However, H274Y has only been reported in N1 subtypes, which indicates that there must be additional key residues that determine H274Y resistance. Furthermore, we found that members of NA serotype N3 also possess Y252, raising the key question as to whether or not H274Y resistance may also be possible for some group 2 NAs. Here, we demonstrate that the H274Y substitution results in mild oseltamivir resistance for N3. Comparative structural analysis of N3, N1, and their 274Y variants indicates that the interaction of residue 296 (H in N1 and nonaromatic for other serotypes) with conserved W295 is another important determinant of oseltamivir resistance.

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Special features of the 2009 pandemic swine-origin influenza A H1N1 hemagglutinin and neuraminidase

Cited by 15 publications

References 49 publications

Structural and functional characterization of neuraminidase-like molecule N10 derived from bat influenza A virus

Structural and functional characterization of neuraminidase-like molecule N10 derived from bat influenza A virus

Influenza neuraminidase operates via a nucleophilic mechanism and can be targeted by covalent inhibitors

Functional and Structural Analysis of Influenza Virus Neuraminidase N3 Offers Further Insight into the Mechanisms of Oseltamivir Resistance

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