Stimulation of mammalian translation initiation factor eIF4A activity by a small molecule inhibitor of eukaryotic translation.
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.
Bordeleau
Marie-Eve
ME
Department of Biochemistry, McIntyre Medical Sciences Building, McGill University, Montreal, QC, Canada H3G 1Y6.
Matthews
James
J
Wojnar
Joanna M
JM
Lindqvist
Lisa
L
Novac
Olivia
O
Jankowsky
Eckhard
E
Sonenberg
Nahum
N
Northcote
Peter
P
Teesdale-Spittle
Paul
P
Pelletier
Jerry
J
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
D004852:Epoxy Compounds; D018942:Macrolides; D012333:RNA, Messenger; D011994:Recombinant Proteins; D013844:Thiazoles; C421324:pateamine A; D039601:Eukaryotic Initiation Factor-4A