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Public Library of Science, PLoS ONE, 2(3), p. e1583, 2008

DOI: 10.1371/journal.pone.0001583

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Selective Pharmacological Targeting of a DEAD Box RNA Helicase

Journal article published in 2008 by Lisa Lindqvist, Monika Oberer ORCID, Regina Cencic, Mikhail Reibarkh, Emily Vogt, Marie-Eve Bordeleau, Assen Marintchev, Junichi Tanaka, Francois Fagotto, Gerhard Wagner, Michael Altmann, Jerry Pelletier
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

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.