title: Selective pharmacological targeting of a DEAD box RNA helicase.
abstract: 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.
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: Lisa
authors.initials: L
authors.lastname: Lindqvist
authors.forename: Monika
authors.initials: M
authors.lastname: Oberer
authors.forename: Mikhail
authors.initials: M
authors.lastname: Reibarkh
authors.forename: Regina
authors.initials: R
authors.lastname: Cencic
authors.forename: Marie-Eve
authors.initials: ME
authors.lastname: Bordeleau
authors.forename: Emily
authors.initials: E
authors.lastname: Vogt
authors.forename: Assen
authors.initials: A
authors.lastname: Marintchev
authors.forename: Junichi
authors.initials: J
authors.lastname: Tanaka
authors.forename: Francois
authors.initials: F
authors.lastname: Fagotto
authors.forename: Michael
authors.initials: M
authors.lastname: Altmann
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wagner
authors.forename: Jerry
authors.initials: J
authors.lastname: Pelletier
mesh_terms: 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*
chemical_list: D013261:Sterols; C510125:hippuristanol; D039601:Eukaryotic Initiation Factor-4A; D053487:DEAD-box RNA Helicases