Anti-frameshifting ligand reduces the conformational plasticity of the SARS virus pseudoknot.
Identifieur interne : 001711 ( Main/Merge ); précédent : 001710; suivant : 001712Anti-frameshifting ligand reduces the conformational plasticity of the SARS virus pseudoknot.
Auteurs : Dustin B. Ritchie [Canada] ; Jingchyuan Soong ; William K A. Sikkema ; Michael T. WoodsideSource :
- Journal of the American Chemical Society [ 1520-5126 ] ; 2014.
Descripteurs français
- KwdFr :
- MESH :
English descriptors
- KwdEn :
- MESH :
- chemical : Ligands.
- chemistry : SARS Virus.
- Amino Acid Motifs, Binding Sites, Frameshifting, Ribosomal, Models, Biological, Molecular Conformation, Molecular Structure.
Abstract
Programmed -1 ribosomal frameshifting (-1 PRF) stimulated by mRNA pseudoknots regulates gene expression in many viruses, making pseudoknots potential targets for anti-viral drugs. The mechanism by which pseudoknots trigger -1 PRF, however, remains controversial, with several competing models. Recent work showed that high -1 PRF efficiency was linked to high pseudoknot conformational plasticity via the formation of alternate conformers. We tested whether pseudoknots bound with an anti-frameshifting ligand exhibited a similar correlation between conformational plasticity and -1 PRF efficiency by measuring the effects of a ligand that was found to inhibit -1 PRF in the SARS coronavirus on the conformational dynamics of the SARS pseudoknot. Using single-molecule force spectroscopy to unfold pseudoknots mechanically, we found that the ligand binding effectively abolished the formation of alternate conformers. This result extends the connection between -1 PRF and conformational dynamics and, moreover, suggests that targeting the conformational dynamics of pseudoknots may be an effective strategy for anti-viral drug design.
DOI: 10.1021/ja410344b
PubMed: 24446874
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Sikkema</name></author><author><name sortKey="Woodside, Michael T" sort="Woodside, Michael T" uniqKey="Woodside M" first="Michael T" last="Woodside">Michael T. 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Ritchie</name><affiliation wicri:level="1"><nlm:affiliation>Department of Physics, University of Alberta , Edmonton, Alberta T6G 2E1, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Physics, University of Alberta , Edmonton, Alberta T6G 2E1</wicri:regionArea><wicri:noRegion>Alberta T6G 2E1</wicri:noRegion></affiliation></author><author><name sortKey="Soong, Jingchyuan" sort="Soong, Jingchyuan" uniqKey="Soong J" first="Jingchyuan" last="Soong">Jingchyuan Soong</name></author><author><name sortKey="Sikkema, William K A" sort="Sikkema, William K A" uniqKey="Sikkema W" first="William K A" last="Sikkema">William K A. Sikkema</name></author><author><name sortKey="Woodside, Michael T" sort="Woodside, Michael T" uniqKey="Woodside M" first="Michael T" last="Woodside">Michael T. Woodside</name></author></analytic><series><title level="j">Journal of the American Chemical Society</title><idno type="eISSN">1520-5126</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amino Acid Motifs</term><term>Binding Sites</term><term>Frameshifting, Ribosomal</term><term>Ligands</term><term>Models, Biological</term><term>Molecular Conformation</term><term>Molecular Structure</term><term>SARS Virus (chemistry)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Conformation moléculaire</term><term>Décalage ribosomique du cadre de lecture</term><term>Ligands</term><term>Modèles biologiques</term><term>Motifs d'acides aminés</term><term>Sites de fixation</term><term>Structure moléculaire</term><term>Virus du SRAS ()</term></keywords><keywords scheme="MESH" type="chemical" xml:lang="en"><term>Ligands</term></keywords><keywords scheme="MESH" qualifier="chemistry" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Amino Acid Motifs</term><term>Binding Sites</term><term>Frameshifting, Ribosomal</term><term>Models, Biological</term><term>Molecular Conformation</term><term>Molecular Structure</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Conformation moléculaire</term><term>Décalage ribosomique du cadre de lecture</term><term>Ligands</term><term>Modèles biologiques</term><term>Motifs d'acides aminés</term><term>Sites de fixation</term><term>Structure moléculaire</term><term>Virus du SRAS</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Programmed -1 ribosomal frameshifting (-1 PRF) stimulated by mRNA pseudoknots regulates gene expression in many viruses, making pseudoknots potential targets for anti-viral drugs. The mechanism by which pseudoknots trigger -1 PRF, however, remains controversial, with several competing models. Recent work showed that high -1 PRF efficiency was linked to high pseudoknot conformational plasticity via the formation of alternate conformers. We tested whether pseudoknots bound with an anti-frameshifting ligand exhibited a similar correlation between conformational plasticity and -1 PRF efficiency by measuring the effects of a ligand that was found to inhibit -1 PRF in the SARS coronavirus on the conformational dynamics of the SARS pseudoknot. Using single-molecule force spectroscopy to unfold pseudoknots mechanically, we found that the ligand binding effectively abolished the formation of alternate conformers. This result extends the connection between -1 PRF and conformational dynamics and, moreover, suggests that targeting the conformational dynamics of pseudoknots may be an effective strategy for anti-viral drug design. </div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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