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...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2008
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/aa2686c7919142e588b948d711ed23c7
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spelling	oai:doaj.org-article:aa2686c7919142e588b948d711ed23c72021-11-25T06:13:25ZSelective pharmacological targeting of a DEAD box RNA helicase.1932-620310.1371/journal.pone.0001583https://doaj.org/article/aa2686c7919142e588b948d711ed23c72008-02-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18270573/?tool=EBIhttps://doaj.org/toc/1932-6203RNA 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.Lisa LindqvistMonika ObererMikhail ReibarkhRegina CencicMarie-Eve BordeleauEmily VogtAssen MarintchevJunichi TanakaFrancois FagottoMichael AltmannGerhard WagnerJerry PelletierPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 3, Iss 2, p e1583 (2008)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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.
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.
format	article
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
title	Selective pharmacological targeting of a DEAD box RNA helicase.
title_short	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_sort	selective pharmacological targeting of a dead box rna helicase.
publisher	Public Library of Science (PLoS)
publishDate	2008
url	https://doaj.org/article/aa2686c7919142e588b948d711ed23c7
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Selective pharmacological targeting of a DEAD box RNA helicase.

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