Selective pharmacological targeting of a DEAD box RNA helicase.
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.
Lindqvist
Lisa
L
Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
Oberer
Monika
M
Reibarkh
Mikhail
M
Cencic
Regina
R
Bordeleau
Marie-Eve
ME
Vogt
Emily
E
Marintchev
Assen
A
Tanaka
Junichi
J
Fagotto
Francois
F
Altmann
Michael
M
Wagner
Gerhard
G
Pelletier
Jerry
J
D000818:Animals; D001665:Binding Sites; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods*; D039601:Eukaryotic Initiation Factor-4A; D051379:Mice; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D013261:Sterols / Q000737:chemistry / Q000494:pharmacology*
D013261:Sterols; C510125:hippuristanol; D039601:Eukaryotic Initiation Factor-4A; D053487:DEAD-box RNA Helicases