Key result
Hippuristanol selectively inhibits the DEAD box RNA helicase eIF4A by binding to amino acids adjacent to and overlapping with two conserved motifs in its carboxy-terminal domain.
Hippuristanol selectively inhibits the DEAD box RNA helicase eIF4A by binding to a specific non-conserved site, providing a mechanism for selective pharmacological targeting of RNA helicases.
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Identifies non-conserved site enabling selective eIF4A inhibition; leaves open therapeutic translation in cardiovascular models.
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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Lindqvist et al. (2008) studied this question. Hippuristanol vs. Vehicle (DMSO) was evaluated on Inhibition of eIF4A RNA-dependent ATPase activity, RNA binding, and helicase activity. Hippuristanol selectively inhibits the DEAD box RNA helicase eIF4A by binding to amino acids adjacent to and overlapping with two conserved motifs in its carboxy-terminal domain.
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