title: Stimulation of mammalian translation initiation factor eIF4A activity by a small molecule inhibitor of eukaryotic translation.
abstract: 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' m7GpppN 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.
authors: Department of Biochemistry, McIntyre Medical Sciences Building, McGill University, Montreal, QC, Canada H3G 1Y6.
authors: Marie-Eve
authors: ME
authors: Bordeleau
authors: James
authors: J
authors: Matthews
authors: Joanna M
authors: JM
authors: Wojnar
authors: Lisa
authors: L
authors: Lindqvist
authors: Olivia
authors: O
authors: Novac
authors: Eckhard
authors: E
authors: Jankowsky
authors: Nahum
authors: N
authors: Sonenberg
authors: Peter
authors: P
authors: Northcote
authors: Paul
authors: P
authors: Teesdale-Spittle
authors: Jerry
authors: J
authors: Pelletier
mesh_terms: D000818:Animals; D002847:Chromatography, Agarose; D004305:Dose-Response Relationship, Drug; D004852:Epoxy Compounds / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004926:Escherichia coli; D039601:Eukaryotic Initiation Factor-4A / Q000378:metabolism*; D018942:Macrolides; D051379:Mice; D014176:Protein Biosynthesis / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism*; D012270:Ribosomes / Q000378:metabolism*; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D004852:Epoxy Compounds; D018942:Macrolides; D012333:RNA, Messenger; D011994:Recombinant Proteins; D013844:Thiazoles; C421324:pateamine A; D039601:Eukaryotic Initiation Factor-4A