Anti-frameshifting ligand reduces the conformational plasticity of the SARS virus pseudoknot.
Identifieur interne : 001705 ( Main/Exploration ); précédent : 001704; suivant : 001706Anti-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
Affiliations:
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Le document en format XML
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<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>
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