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Mapping the sequence mutations of the 2009 H1N1 influenza A virus neuraminidase relative to drug and antibody binding sites.

Maurer-Stroh S, Ma J, Lee RT, Sirota FL, Eisenhaber F - Biol. Direct (2009)

Bottom Line: Homology-based 3D structure modeling reveals that the novel mutations are preferentially located at the protein surface and do not interfere with the active site.The latter is the binding cavity for 3 currently used neuraminidase inhibitors: oseltamivir (Tamiflu), zanamivir (Relenza) and peramivir; thus, the drugs should remain effective for treatment.Aravind.

View Article: PubMed Central - HTML - PubMed

Affiliation: Biomolecular Function Discovery Division, Bioinformatics Institute (BII), Agency for Science Technology and Research (A*STAR), Singapore. sebastianms@bii.a-star.edu.sg

ABSTRACT

Unlabelled: In this work, we study the consequences of sequence variations of the "2009 H1N1" (swine or Mexican flu) influenza A virus strain neuraminidase for drug treatment and vaccination. We find that it is phylogenetically more closely related to European H1N1 swine flu and H5N1 avian flu rather than to the H1N1 counterparts in the Americas. Homology-based 3D structure modeling reveals that the novel mutations are preferentially located at the protein surface and do not interfere with the active site. The latter is the binding cavity for 3 currently used neuraminidase inhibitors: oseltamivir (Tamiflu), zanamivir (Relenza) and peramivir; thus, the drugs should remain effective for treatment. However, the antigenic regions of the neuraminidase relevant for vaccine development, serological typing and passive antibody treatment can differ from those of previous strains and already vary among patients.

Reviewers: This article was reviewed by Sandor Pongor and L. Aravind.

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Alignment of the NA domain of the 2009 H1N1 strain with the sequences in crystal structures of H5N1 avian flu as well as H1N1 from the 1918 Spanish flu. Residues within 3 Å of the bound drug are indicated with "#", while residues that are different in the new strain compared to both other structures are marked with "@".Intra-strain variation (Flex [AA] in the first annotation line) is displayed as the respective mutated residue in capital letters if found in multiple patients (e.g. D for the N248D substitution) or lower-case (e.g. "i" for V241I) for single occurrences. In the second annotation row, antigenic regions are labelled as "*". Residues with < 3 Å contact to antibodies are labelled "A" for interactions derived from PDB:1ncb, "B" from both PDB:1ncb and PDB:1nmb, "C" from PDB:1nmb and "D" from PDB:2aep.
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Figure 5: Alignment of the NA domain of the 2009 H1N1 strain with the sequences in crystal structures of H5N1 avian flu as well as H1N1 from the 1918 Spanish flu. Residues within 3 Å of the bound drug are indicated with "#", while residues that are different in the new strain compared to both other structures are marked with "@".Intra-strain variation (Flex [AA] in the first annotation line) is displayed as the respective mutated residue in capital letters if found in multiple patients (e.g. D for the N248D substitution) or lower-case (e.g. "i" for V241I) for single occurrences. In the second annotation row, antigenic regions are labelled as "*". Residues with < 3 Å contact to antibodies are labelled "A" for interactions derived from PDB:1ncb, "B" from both PDB:1ncb and PDB:1nmb, "C" from PDB:1nmb and "D" from PDB:2aep.

Mentions: Next, we compared the sequences of the new strain with the related H5N1 from avian flu and H1N1 from the Spanish flu (Figure 5). Among 387 residues that were structurally modelled, the "2009 H1N1" neuraminidase differs from the other two in 21 positions. The mapping to the structure (Figure 4B) shows that the novel sequence mutations are distributed all around the surface of the molecule leaving the hydrophobic core, but also the catalytic site, essentially untouched. Importantly, none of the new mutations appears sufficiently close to affect the drug binding pocket. For example, all 17 residues within 3 Å of the zanamivir molecule bound to the active site are fully conserved among all three strains. The closest mutation is the conservative V149I substitution at a distance of ~10 Å to zanamivir and ~7 Å to oseltavimir.


Mapping the sequence mutations of the 2009 H1N1 influenza A virus neuraminidase relative to drug and antibody binding sites.

Maurer-Stroh S, Ma J, Lee RT, Sirota FL, Eisenhaber F - Biol. Direct (2009)

Alignment of the NA domain of the 2009 H1N1 strain with the sequences in crystal structures of H5N1 avian flu as well as H1N1 from the 1918 Spanish flu. Residues within 3 Å of the bound drug are indicated with "#", while residues that are different in the new strain compared to both other structures are marked with "@".Intra-strain variation (Flex [AA] in the first annotation line) is displayed as the respective mutated residue in capital letters if found in multiple patients (e.g. D for the N248D substitution) or lower-case (e.g. "i" for V241I) for single occurrences. In the second annotation row, antigenic regions are labelled as "*". Residues with < 3 Å contact to antibodies are labelled "A" for interactions derived from PDB:1ncb, "B" from both PDB:1ncb and PDB:1nmb, "C" from PDB:1nmb and "D" from PDB:2aep.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2691737&req=5

Figure 5: Alignment of the NA domain of the 2009 H1N1 strain with the sequences in crystal structures of H5N1 avian flu as well as H1N1 from the 1918 Spanish flu. Residues within 3 Å of the bound drug are indicated with "#", while residues that are different in the new strain compared to both other structures are marked with "@".Intra-strain variation (Flex [AA] in the first annotation line) is displayed as the respective mutated residue in capital letters if found in multiple patients (e.g. D for the N248D substitution) or lower-case (e.g. "i" for V241I) for single occurrences. In the second annotation row, antigenic regions are labelled as "*". Residues with < 3 Å contact to antibodies are labelled "A" for interactions derived from PDB:1ncb, "B" from both PDB:1ncb and PDB:1nmb, "C" from PDB:1nmb and "D" from PDB:2aep.
Mentions: Next, we compared the sequences of the new strain with the related H5N1 from avian flu and H1N1 from the Spanish flu (Figure 5). Among 387 residues that were structurally modelled, the "2009 H1N1" neuraminidase differs from the other two in 21 positions. The mapping to the structure (Figure 4B) shows that the novel sequence mutations are distributed all around the surface of the molecule leaving the hydrophobic core, but also the catalytic site, essentially untouched. Importantly, none of the new mutations appears sufficiently close to affect the drug binding pocket. For example, all 17 residues within 3 Å of the zanamivir molecule bound to the active site are fully conserved among all three strains. The closest mutation is the conservative V149I substitution at a distance of ~10 Å to zanamivir and ~7 Å to oseltavimir.

Bottom Line: Homology-based 3D structure modeling reveals that the novel mutations are preferentially located at the protein surface and do not interfere with the active site.The latter is the binding cavity for 3 currently used neuraminidase inhibitors: oseltamivir (Tamiflu), zanamivir (Relenza) and peramivir; thus, the drugs should remain effective for treatment.Aravind.

View Article: PubMed Central - HTML - PubMed

Affiliation: Biomolecular Function Discovery Division, Bioinformatics Institute (BII), Agency for Science Technology and Research (A*STAR), Singapore. sebastianms@bii.a-star.edu.sg

ABSTRACT

Unlabelled: In this work, we study the consequences of sequence variations of the "2009 H1N1" (swine or Mexican flu) influenza A virus strain neuraminidase for drug treatment and vaccination. We find that it is phylogenetically more closely related to European H1N1 swine flu and H5N1 avian flu rather than to the H1N1 counterparts in the Americas. Homology-based 3D structure modeling reveals that the novel mutations are preferentially located at the protein surface and do not interfere with the active site. The latter is the binding cavity for 3 currently used neuraminidase inhibitors: oseltamivir (Tamiflu), zanamivir (Relenza) and peramivir; thus, the drugs should remain effective for treatment. However, the antigenic regions of the neuraminidase relevant for vaccine development, serological typing and passive antibody treatment can differ from those of previous strains and already vary among patients.

Reviewers: This article was reviewed by Sandor Pongor and L. Aravind.

Show MeSH
Related in: MedlinePlus