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 prototyp...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2008-02-01
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| Series: | PLoS ONE |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18270573/?tool=EBI |
| _version_ | 1830408651228053504 |
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| author | Lisa Lindqvist Monika Oberer Mikhail Reibarkh Regina Cencic Marie-Eve Bordeleau Emily Vogt Assen Marintchev Junichi Tanaka Francois Fagotto Michael Altmann Gerhard Wagner Jerry Pelletier |
| author_facet | Lisa Lindqvist Monika Oberer Mikhail Reibarkh Regina Cencic Marie-Eve Bordeleau Emily Vogt Assen Marintchev Junichi Tanaka Francois Fagotto Michael Altmann Gerhard Wagner Jerry Pelletier |
| author_sort | Lisa Lindqvist |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T18:55:49Z |
| format | Article |
| id | doaj.art-aa2686c7919142e588b948d711ed23c7 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-20T18:55:49Z |
| publishDate | 2008-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-aa2686c7919142e588b948d711ed23c72022-12-21T19:29:30ZengPublic Library of Science (PLoS)PLoS ONE1932-62032008-02-0132e158310.1371/journal.pone.0001583Selective pharmacological targeting of a DEAD box RNA helicase.Lisa LindqvistMonika ObererMikhail ReibarkhRegina CencicMarie-Eve BordeleauEmily VogtAssen MarintchevJunichi TanakaFrancois FagottoMichael AltmannGerhard WagnerJerry PelletierRNA 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.https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18270573/?tool=EBI |
| spellingShingle | Lisa Lindqvist Monika Oberer Mikhail Reibarkh Regina Cencic Marie-Eve Bordeleau Emily Vogt Assen Marintchev Junichi Tanaka Francois Fagotto Michael Altmann Gerhard Wagner Jerry Pelletier Selective pharmacological targeting of a DEAD box RNA helicase. PLoS ONE |
| title | Selective pharmacological targeting of a DEAD box RNA helicase. |
| title_full | Selective pharmacological targeting of a DEAD box RNA helicase. |
| title_fullStr | Selective pharmacological targeting of a DEAD box RNA helicase. |
| title_full_unstemmed | Selective pharmacological targeting of a DEAD box RNA helicase. |
| title_short | Selective pharmacological targeting of a DEAD box RNA helicase. |
| title_sort | selective pharmacological targeting of a dead box rna helicase |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18270573/?tool=EBI |
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