Selective pharmacological targeting of a DEAD box RNA helicase

Lindqvist, Lisa; Oberer, Monika; Reibarkh, Mikhail; Cencic, Regina; Bordeleau, Marie-Eve; Vogt, Emily; Marintchev, Assen; Tanaka, Junichi; Fagotto, Francois; Altmann, Michael; Wagner, Gerhard; Pelletier, Jerry (2008). Selective pharmacological targeting of a DEAD box RNA helicase. PLoS ONE, 3(2), e1583. Lawrence, Kans.: Public Library of Science 10.1371/journal.pone.0001583

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Altmann, Michael

ISSN:

1932-6203

ISBN:

18270573

Publisher:

Public Library of Science

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 15:05

Last Modified:

04 May 2014 23:20

Publisher DOI:

10.1371/journal.pone.0001583

PubMed ID:

18270573

Web of Science ID:

000260535900019

URI:

https://boris.unibe.ch/id/eprint/28313 (FactScience: 119820)

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