Anti-frameshifting ligand reduces the conformational plasticity of the SARS virus pseudoknot.
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.
Department of Physics, University of Alberta , Edmonton, Alberta T6G 2E1, Canada.
Dustin B
DB
Ritchie
Jingchyuan
J
Soong
William K A
WK
Sikkema
Michael T
MT
Woodside
D020816:Amino Acid Motifs; D001665:Binding Sites; D018965:Frameshifting, Ribosomal; D008024:Ligands; D008954:Models, Biological; D008968:Molecular Conformation; D015394:Molecular Structure; D045473:Severe acute respiratory syndrome-related coronavirus / Q000737:chemistry*
D008024:Ligands