Tuesday, January 28, 2014

Anti-frameshifting ligand reduces the conformational plasticity of the SARS virus pseudoknot

Dustin B Ritchie , Jingchyuan Soong , William Sikkema , and Michael T. Woodside

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 which 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.

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