Computational analysis and determination of a highly conserved surface exposed segment in H5N1 avian flu and H1N1 swine flu neuraminidase
Identifieur interne : 000862 ( Pmc/Checkpoint ); précédent : 000861; suivant : 000863Computational analysis and determination of a highly conserved surface exposed segment in H5N1 avian flu and H1N1 swine flu neuraminidase
Auteurs : Ambarnil Ghosh [Inde] ; Ashesh Nandy [Inde] ; Papiya Nandy [Inde]Source :
- BMC Structural Biology [ 1472-6807 ] ; 2010.
Abstract
Catalytic activity of influenza neuraminidase (NA) facilitates elution of progeny virions from infected cells and prevents their self-aggregation mediated by the catalytic site located in the body region. Research on the active site of the molecule has led to development of effective inhibitors like oseltamivir, zanamivir etc, but the high rate of mutation and interspecies reassortment in viral sequences and the recent reports of oseltamivir resistant strains underlines the importance of determining additional target sites for developing future antiviral compounds. In a recent computational study of 173 H5N1 NA gene sequences we had identified a 50-base highly conserved region in 3'-terminal end of the NA gene.
We extend the graphical and numerical analyses to a larger number of H5N1 NA sequences (514) and H1N1 swine flu sequences (425) accessed from GenBank. We use a 2D graphical representation model for the gene sequences and a Graphical Sliding Window Method (GSWM) for protein sequences scanning the sequences as a block of 16 amino acids at a time. Using a protein sequence descriptor defined in our model, the protein sliding scan method allowed us to compare the different strains for block level variability, which showed significant statistical correlation to average solvent accessibility of the residue blocks; single amino acid position variability results in no correlation, indicating the impact of stretch variability in chemical environment. Close to the C-terminal end the GSWM showed less descriptor-variability with increased average solvent accessibility (ASA) that is also supported by conserved predicted secondary structure of 3' terminal RNA and visual evidence from 3D crystallographic structure.
The identified terminal segment, strongly conserved in both RNA and protein sequences, is especially significant as it is surface exposed and structural chemistry reveals the probable role of this stretch in tetrameric stabilization. It could also participate in other biological processes associated with conserved surface residues. A RNA double hairpin secondary structure found in this segment in a majority of the H5N1 strains also supports this observation. In this paper we propose this conserved region as a probable site for designing inhibitors for broad-spectrum pandemic control of flu viruses with similar NA structure.
Url:
DOI: 10.1186/1472-6807-10-6
PubMed: 20170556
PubMed Central: 2836360
Affiliations:
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xml:lang="fr">Inde</country><wicri:regionArea>School of Environmental Studies, Jadavpur University, Jadavpur, Kolkata 700032</wicri:regionArea><wicri:noRegion>Kolkata 700032</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="I3">Centre for Interdisciplinary Research and Education, Jodhpur Park, Kolkata 700068, India</nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea>Centre for Interdisciplinary Research and Education, Jodhpur Park, Kolkata 700068</wicri:regionArea><wicri:noRegion>Kolkata 700068</wicri:noRegion></affiliation></author><author><name sortKey="Nandy, Papiya" sort="Nandy, Papiya" uniqKey="Nandy P" first="Papiya" last="Nandy">Papiya Nandy</name><affiliation wicri:level="1"><nlm:aff id="I1">Physics Department, Jadavpur University, Jadavpur, Kolkata 700032, India</nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea>Physics Department, Jadavpur University, Jadavpur, Kolkata 700032</wicri:regionArea><wicri:noRegion>Kolkata 700032</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">20170556</idno><idno type="pmc">2836360</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2836360</idno><idno type="RBID">PMC:2836360</idno><idno type="doi">10.1186/1472-6807-10-6</idno><date when="2010">2010</date><idno type="wicri:Area/Pmc/Corpus">000815</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000815</idno><idno type="wicri:Area/Pmc/Curation">000815</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000815</idno><idno type="wicri:Area/Pmc/Checkpoint">000862</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000862</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Computational analysis and determination of a highly conserved surface exposed segment in H5N1 avian flu and H1N1 swine flu neuraminidase</title><author><name sortKey="Ghosh, Ambarnil" sort="Ghosh, Ambarnil" uniqKey="Ghosh A" first="Ambarnil" last="Ghosh">Ambarnil Ghosh</name><affiliation wicri:level="1"><nlm:aff id="I1">Physics Department, Jadavpur University, Jadavpur, Kolkata 700032, India</nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea>Physics Department, Jadavpur University, Jadavpur, Kolkata 700032</wicri:regionArea><wicri:noRegion>Kolkata 700032</wicri:noRegion></affiliation></author><author><name sortKey="Nandy, Ashesh" sort="Nandy, Ashesh" uniqKey="Nandy A" first="Ashesh" last="Nandy">Ashesh Nandy</name><affiliation wicri:level="1"><nlm:aff id="I2">School of Environmental Studies, Jadavpur University, Jadavpur, Kolkata 700032, India</nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea>School of Environmental Studies, Jadavpur University, Jadavpur, Kolkata 700032</wicri:regionArea><wicri:noRegion>Kolkata 700032</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="I3">Centre for Interdisciplinary Research and Education, Jodhpur Park, Kolkata 700068, India</nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea>Centre for Interdisciplinary Research and Education, Jodhpur Park, Kolkata 700068</wicri:regionArea><wicri:noRegion>Kolkata 700068</wicri:noRegion></affiliation></author><author><name sortKey="Nandy, Papiya" sort="Nandy, Papiya" uniqKey="Nandy P" first="Papiya" last="Nandy">Papiya Nandy</name><affiliation wicri:level="1"><nlm:aff id="I1">Physics Department, Jadavpur University, Jadavpur, Kolkata 700032, India</nlm:aff><country xml:lang="fr">Inde</country><wicri:regionArea>Physics Department, Jadavpur University, Jadavpur, Kolkata 700032</wicri:regionArea><wicri:noRegion>Kolkata 700032</wicri:noRegion></affiliation></author></analytic><series><title level="j">BMC Structural Biology</title><idno type="eISSN">1472-6807</idno><imprint><date when="2010">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>Catalytic activity of influenza neuraminidase (NA) facilitates elution of progeny virions from infected cells and prevents their self-aggregation mediated by the catalytic site located in the body region. Research on the active site of the molecule has led to development of effective inhibitors like oseltamivir, zanamivir etc, but the high rate of mutation and interspecies reassortment in viral sequences and the recent reports of oseltamivir resistant strains underlines the importance of determining additional target sites for developing future antiviral compounds. In a recent computational study of 173 H5N1 NA gene sequences we had identified a 50-base highly conserved region in 3'-terminal end of the NA gene.</p></sec><sec><title>Results</title><p>We extend the graphical and numerical analyses to a larger number of H5N1 NA sequences (514) and H1N1 swine flu sequences (425) accessed from GenBank. We use a 2D graphical representation model for the gene sequences and a Graphical Sliding Window Method (GSWM) for protein sequences scanning the sequences as a block of 16 amino acids at a time. Using a protein sequence descriptor defined in our model, the protein sliding scan method allowed us to compare the different strains for block level variability, which showed significant statistical correlation to average solvent accessibility of the residue blocks; single amino acid position variability results in no correlation, indicating the impact of stretch variability in chemical environment. Close to the C-terminal end the GSWM showed less descriptor-variability with increased average solvent accessibility (ASA) that is also supported by conserved predicted secondary structure of 3' terminal RNA and visual evidence from 3D crystallographic structure.</p></sec><sec><title>Conclusion</title><p>The identified terminal segment, strongly conserved in both RNA and protein sequences, is especially significant as it is surface exposed and structural chemistry reveals the probable role of this stretch in tetrameric stabilization. It could also participate in other biological processes associated with conserved surface residues. A RNA double hairpin secondary structure found in this segment in a majority of the H5N1 strains also supports this observation. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">BMC Struct Biol</journal-id><journal-title-group><journal-title>BMC Structural Biology</journal-title></journal-title-group><issn pub-type="epub">1472-6807</issn><publisher><publisher-name>BioMed Central</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">20170556</article-id><article-id pub-id-type="pmc">2836360</article-id><article-id pub-id-type="publisher-id">1472-6807-10-6</article-id><article-id pub-id-type="doi">10.1186/1472-6807-10-6</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research article</subject></subj-group></article-categories><title-group><article-title>Computational analysis and determination of a highly conserved surface exposed segment in H5N1 avian flu and H1N1 swine flu neuraminidase</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes" id="A1"><name><surname>Ghosh</surname><given-names>Ambarnil</given-names></name><xref ref-type="aff" rid="I1">1</xref><email>ambarnil_ghosh@yahoo.co.in</email></contrib><contrib contrib-type="author" id="A2"><name><surname>Nandy</surname><given-names>Ashesh</given-names></name><xref ref-type="aff" rid="I2">2</xref><xref ref-type="aff" rid="I3">3</xref><email>anandy43@yahoo.com</email></contrib><contrib contrib-type="author" id="A3"><name><surname>Nandy</surname><given-names>Papiya</given-names></name><xref ref-type="aff" rid="I1">1</xref><email>pnandy00@yahoo.com</email></contrib></contrib-group><aff id="I1"><label>1</label>Physics Department, Jadavpur University, Jadavpur, Kolkata 700032, India</aff><aff id="I2"><label>2</label>School of Environmental Studies, Jadavpur University, Jadavpur, Kolkata 700032, India</aff><aff id="I3"><label>3</label>Centre for Interdisciplinary Research and Education, Jodhpur Park, Kolkata 700068, India</aff><pub-date pub-type="collection"><year>2010</year></pub-date><pub-date pub-type="epub"><day>22</day><month>2</month><year>2010</year></pub-date><volume>10</volume><fpage>6</fpage><lpage>6</lpage><history><date date-type="received"><day>7</day><month>8</month><year>2009</year></date><date date-type="accepted"><day>22</day><month>2</month><year>2010</year></date></history><permissions><copyright-statement>Copyright ©2010 Ghosh et al; licensee BioMed Central Ltd.</copyright-statement><copyright-year>2010</copyright-year><copyright-holder>Ghosh et al; licensee BioMed Central Ltd.</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/2.0"><license-p>This is an Open Access article distributed under the terms of the Creative Commons Attribution License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/2.0">http://creativecommons.org/licenses/by/2.0</ext-link>), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><self-uri xlink:href="http://www.biomedcentral.com/1472-6807/10/6"></self-uri><abstract><sec><title>Background</title><p>Catalytic activity of influenza neuraminidase (NA) facilitates elution of progeny virions from infected cells and prevents their self-aggregation mediated by the catalytic site located in the body region. Research on the active site of the molecule has led to development of effective inhibitors like oseltamivir, zanamivir etc, but the high rate of mutation and interspecies reassortment in viral sequences and the recent reports of oseltamivir resistant strains underlines the importance of determining additional target sites for developing future antiviral compounds. In a recent computational study of 173 H5N1 NA gene sequences we had identified a 50-base highly conserved region in 3'-terminal end of the NA gene.</p></sec><sec><title>Results</title><p>We extend the graphical and numerical analyses to a larger number of H5N1 NA sequences (514) and H1N1 swine flu sequences (425) accessed from GenBank. We use a 2D graphical representation model for the gene sequences and a Graphical Sliding Window Method (GSWM) for protein sequences scanning the sequences as a block of 16 amino acids at a time. Using a protein sequence descriptor defined in our model, the protein sliding scan method allowed us to compare the different strains for block level variability, which showed significant statistical correlation to average solvent accessibility of the residue blocks; single amino acid position variability results in no correlation, indicating the impact of stretch variability in chemical environment. Close to the C-terminal end the GSWM showed less descriptor-variability with increased average solvent accessibility (ASA) that is also supported by conserved predicted secondary structure of 3' terminal RNA and visual evidence from 3D crystallographic structure.</p></sec><sec><title>Conclusion</title><p>The identified terminal segment, strongly conserved in both RNA and protein sequences, is especially significant as it is surface exposed and structural chemistry reveals the probable role of this stretch in tetrameric stabilization. It could also participate in other biological processes associated with conserved surface residues. A RNA double hairpin secondary structure found in this segment in a majority of the H5N1 strains also supports this observation. In this paper we propose this conserved region as a probable site for designing inhibitors for broad-spectrum pandemic control of flu viruses with similar NA structure.</p></sec></abstract></article-meta></front></pmc><affiliations><list><country><li>Inde</li></country></list><tree><country name="Inde"><noRegion><name sortKey="Ghosh, Ambarnil" sort="Ghosh, Ambarnil" uniqKey="Ghosh A" first="Ambarnil" last="Ghosh">Ambarnil Ghosh</name></noRegion><name sortKey="Nandy, Ashesh" sort="Nandy, Ashesh" uniqKey="Nandy A" first="Ashesh" last="Nandy">Ashesh Nandy</name><name sortKey="Nandy, Ashesh" sort="Nandy, Ashesh" uniqKey="Nandy A" first="Ashesh" last="Nandy">Ashesh Nandy</name><name sortKey="Nandy, Papiya" sort="Nandy, Papiya" uniqKey="Nandy P" first="Papiya" last="Nandy">Papiya Nandy</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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