Selective pharmacological targeting of a DEAD box RNA helicase
| Autor: | François Fagotto, Emily Vogt, Mikhail Reibarkh, Monika Oberer, Assen Marintchev, Michael Altmann, Lisa M Lindqvist, Gerhard Wagner, Regina Cencic, Marie-Eve Bordeleau, Junichi Tanaka, Jerry Pelletier |
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| Rok vydání: | 2008 |
| Předmět: |
DEAD box
Science Ribosome biogenesis Ribosome DEAD-box RNA Helicases 03 medical and health sciences Mice 0302 clinical medicine Drug Delivery Systems Chemical Biology Animals Nuclear Magnetic Resonance Biomolecular 030304 developmental biology Genetics 0303 health sciences Multidisciplinary Binding Sites biology Helicase Translation (biology) RNA Helicase A Cell biology Sterols 030220 oncology & carcinogenesis eIF4A RNA splicing Eukaryotic Initiation Factor-4A Mutation biology.protein Medicine Biochemistry/Drug Discovery Biochemistry/Transcription and Translation Research Article Protein Binding |
| Zdroj: | PloS one PLoS ONE PLoS ONE, Vol 3, Iss 2, p e1583 (2008) |
| DOI: | 10.1371/journal.pone.0001583 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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