Selective pharmacological targeting of a DEAD box RNA helicase.
Web of Science
AuthorLindqvist, L; Oberer, M; Reibarkh, M; Cencic, R; Bordeleau, M-E; Vogt, E; Marintchev, A; Tanaka, J; Fagotto, F; Altmann, M; ...
Source TitlePLoS One
PublisherPublic Library of Science (PLoS)
University of Melbourne Author/sLindqvist, Lisa
AffiliationMedical Biology (W.E.H.I.)
Document TypeJournal Article
CitationsLindqvist, L., Oberer, M., Reibarkh, M., Cencic, R., Bordeleau, M. -E., Vogt, E., Marintchev, A., Tanaka, J., Fagotto, F., Altmann, M., Wagner, G. & Pelletier, J. (2008). Selective pharmacological targeting of a DEAD box RNA helicase.. PLoS One, 3 (2), pp.e1583-. https://doi.org/10.1371/journal.pone.0001583.
Access StatusOpen Access
Open Access at PMChttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2216682
RNA helicases represent a large family of proteins implicated in many biological processes including ribosome biogenesis, splicing, translation and mRNA degradation. However, these proteins have little substrate specificity, making inhibition of selected helicases a challenging problem. The prototypical DEAD box RNA helicase, eIF4A, works in conjunction with other translation factors to prepare mRNA templates for ribosome recruitment during translation initiation. Herein, we provide insight into the selectivity of a small molecule inhibitor of eIF4A, hippuristanol. This coral-derived natural product binds to amino acids adjacent to, and overlapping with, two conserved motifs present in the carboxy-terminal domain of eIF4A. Mutagenesis of amino acids within this region allowed us to alter the hippuristanol-sensitivity of eIF4A and undertake structure/function studies. Our results provide an understanding into how selective targeting of RNA helicases for pharmacological intervention can be achieved.
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