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HIVToolbox, an integrated web application for investigating HIV.

Sargeant D, Deverasetty S, Luo Y, Villahoz Baleta A, Zobrist S, Rathnayake V, Russo JC, Vyas J, Muesing MA, Schiller MR - PLoS ONE (2011)

Bottom Line: HIV-1 integrase protein was used as a case study to show the utility of this application.We show how data integration facilitates identification of new questions and hypotheses much more rapid and convenient than current approaches using isolated repositories.Several new hypotheses for integrase were created as an example, and we experimentally confirmed a predicted CK2 phosphorylation site.

View Article: PubMed Central - PubMed

Affiliation: School of Life Sciences, University of Nevada Las Vegas, Las Vegas, Nevada, United States of America.

ABSTRACT
Many bioinformatic databases and applications focus on a limited domain of knowledge federating links to information in other databases. This segregated data structure likely limits our ability to investigate and understand complex biological systems. To facilitate research, therefore, we have built HIVToolbox, which integrates much of the knowledge about HIV proteins and allows virologists and structural biologists to access sequence, structure, and functional relationships in an intuitive web application. HIV-1 integrase protein was used as a case study to show the utility of this application. We show how data integration facilitates identification of new questions and hypotheses much more rapid and convenient than current approaches using isolated repositories. Several new hypotheses for integrase were created as an example, and we experimentally confirmed a predicted CK2 phosphorylation site. Weblink: [http://hivtoolbox.bio-toolkit.com].

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Analysis of Integrase model tetramers and hetero-octamers.Output of HIVToolbox showing surface plots of IN structural models. (A, B) IN tetramers showing domain organization (left panels) and locations of actives site residues (royal blue), proposed viral DNA binding grooves (yellow lines), proposed genomic DNA binding channel (red line), and zinc binding sites (cyan). Yellow numbers indicate the subunit too which the domain belongs. (C) IN:LEDGF hetero-octamers models showing organization of proteins (left panel) and proposed DNA binding groove (middle panel, red line). LEDGF subunits are colored grey. (D) An end-on view of the proposed host DNA binding channel in the IN:LEGDF hetero-octamer model shown in (C) (red circle).
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pone-0020122-g003: Analysis of Integrase model tetramers and hetero-octamers.Output of HIVToolbox showing surface plots of IN structural models. (A, B) IN tetramers showing domain organization (left panels) and locations of actives site residues (royal blue), proposed viral DNA binding grooves (yellow lines), proposed genomic DNA binding channel (red line), and zinc binding sites (cyan). Yellow numbers indicate the subunit too which the domain belongs. (C) IN:LEDGF hetero-octamers models showing organization of proteins (left panel) and proposed DNA binding groove (middle panel, red line). LEDGF subunits are colored grey. (D) An end-on view of the proposed host DNA binding channel in the IN:LEGDF hetero-octamer model shown in (C) (red circle).

Mentions: To demonstrate different types of analysis supported by HIVToolbox, integrase (IN) was analyzed as a case study. IN is a well-studied multidomain and oligomeric viral protein that is essential for integrating viral DNA into the host genome, for viral infectivity, and for which potent inhibitors of its strand transfer function are chemotherapeutically available. Examples of how HIVToolbox can assist with hypothesis generation, experimental design, interpretation of results, and evaluation of structures and structural models are in Figs. 1–4, Table 1. One of the advantages is that data from many separate studies can be readily interpreted simultaneously. Several new hypotheses concerning IN complexes, DNA binding, nuclear import, and LEDGF binding are discussed. Since there is no structure of full length IN, these analyses also involved a number of different IN structural models that were generated by superposition of common regions in experimental IN structures (see Methods). This is an approach that was previously used by Wang et al. to propose a structure of the full IN monomer [8]. The models are available on the HIVToolbox website. We also used a recent structural model of the Prototypic Foamy Virus IN (PFV IN) to create a HIV-1 IN model, and analyzed this model with HIVToolbox [9].


HIVToolbox, an integrated web application for investigating HIV.

Sargeant D, Deverasetty S, Luo Y, Villahoz Baleta A, Zobrist S, Rathnayake V, Russo JC, Vyas J, Muesing MA, Schiller MR - PLoS ONE (2011)

Analysis of Integrase model tetramers and hetero-octamers.Output of HIVToolbox showing surface plots of IN structural models. (A, B) IN tetramers showing domain organization (left panels) and locations of actives site residues (royal blue), proposed viral DNA binding grooves (yellow lines), proposed genomic DNA binding channel (red line), and zinc binding sites (cyan). Yellow numbers indicate the subunit too which the domain belongs. (C) IN:LEDGF hetero-octamers models showing organization of proteins (left panel) and proposed DNA binding groove (middle panel, red line). LEDGF subunits are colored grey. (D) An end-on view of the proposed host DNA binding channel in the IN:LEGDF hetero-octamer model shown in (C) (red circle).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3102074&req=5

pone-0020122-g003: Analysis of Integrase model tetramers and hetero-octamers.Output of HIVToolbox showing surface plots of IN structural models. (A, B) IN tetramers showing domain organization (left panels) and locations of actives site residues (royal blue), proposed viral DNA binding grooves (yellow lines), proposed genomic DNA binding channel (red line), and zinc binding sites (cyan). Yellow numbers indicate the subunit too which the domain belongs. (C) IN:LEDGF hetero-octamers models showing organization of proteins (left panel) and proposed DNA binding groove (middle panel, red line). LEDGF subunits are colored grey. (D) An end-on view of the proposed host DNA binding channel in the IN:LEGDF hetero-octamer model shown in (C) (red circle).
Mentions: To demonstrate different types of analysis supported by HIVToolbox, integrase (IN) was analyzed as a case study. IN is a well-studied multidomain and oligomeric viral protein that is essential for integrating viral DNA into the host genome, for viral infectivity, and for which potent inhibitors of its strand transfer function are chemotherapeutically available. Examples of how HIVToolbox can assist with hypothesis generation, experimental design, interpretation of results, and evaluation of structures and structural models are in Figs. 1–4, Table 1. One of the advantages is that data from many separate studies can be readily interpreted simultaneously. Several new hypotheses concerning IN complexes, DNA binding, nuclear import, and LEDGF binding are discussed. Since there is no structure of full length IN, these analyses also involved a number of different IN structural models that were generated by superposition of common regions in experimental IN structures (see Methods). This is an approach that was previously used by Wang et al. to propose a structure of the full IN monomer [8]. The models are available on the HIVToolbox website. We also used a recent structural model of the Prototypic Foamy Virus IN (PFV IN) to create a HIV-1 IN model, and analyzed this model with HIVToolbox [9].

Bottom Line: HIV-1 integrase protein was used as a case study to show the utility of this application.We show how data integration facilitates identification of new questions and hypotheses much more rapid and convenient than current approaches using isolated repositories.Several new hypotheses for integrase were created as an example, and we experimentally confirmed a predicted CK2 phosphorylation site.

View Article: PubMed Central - PubMed

Affiliation: School of Life Sciences, University of Nevada Las Vegas, Las Vegas, Nevada, United States of America.

ABSTRACT
Many bioinformatic databases and applications focus on a limited domain of knowledge federating links to information in other databases. This segregated data structure likely limits our ability to investigate and understand complex biological systems. To facilitate research, therefore, we have built HIVToolbox, which integrates much of the knowledge about HIV proteins and allows virologists and structural biologists to access sequence, structure, and functional relationships in an intuitive web application. HIV-1 integrase protein was used as a case study to show the utility of this application. We show how data integration facilitates identification of new questions and hypotheses much more rapid and convenient than current approaches using isolated repositories. Several new hypotheses for integrase were created as an example, and we experimentally confirmed a predicted CK2 phosphorylation site. Weblink: [http://hivtoolbox.bio-toolkit.com].

Show MeSH