Marie-Eve Bordeleau1, James Matthews1, Joanna M. Wojnar1, Lisa Lindqvist1, Olivia Novac1, Eckhard Jankowsky1, Nahum Sonenberg1, Peter T. Northcote1, Paul Teesdale‐Spittle1, Jerry Pelletier1
1Department of Biochemistry and McGill Cancer Center, McIntyre Medical Sciences Building, McGill University, Montreal, QC, Canada H3G 1Y6; Schools of Biological Sciences and Chemical and Physical Sciences, Victoria University of Wellington, Wellington, New Zealand; and Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH 44106
Tóm tắt
RNA helicases are the largest group of enzymes in eukaryotic RNA metabolism. The DEXD/H-box putative RNA helicases form the helicase superfamily II, whose members are defined by seven highly conserved amino acid motifs, making specific targeting of selected members a challenging pharmacological problem. The translation initiation factor eIF4A is the prototypical DEAD-box RNA helicase that works in conjunction with eIF4B and eIF4H and as a subunit of eIF4F to prepare the mRNA template for ribosome binding, possibly by unwinding the secondary structure proximal to the 5′ m
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GpppN cap structure. We report the identification and characterization of a small molecule inhibitor of eukaryotic translation initiation that acts in an unusual manner by stimulating eIF4A-associated activities. Our results suggest that proper control of eIF4A helicase activity is necessary for efficient ribosome binding and demonstrate the feasibility of selectively targeting DEAD-box RNA helicases with small molecules.
