Stimulation of mammalian translation initiation factor eIF4A activity by a small molecule inhibitor of eukaryotic translation
Stimulation of mammalian translation initiation factor eIF4A activity by a small molecule inhibitor of eukaryotic translation
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DOI：
10.1073/pnas.0504249102
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发表时间：
2005-07-26
影响因子：
11.1
通讯作者：
Pelletier, J
中科院分区：
文献类型：
--
作者：
Bordeleau, ME;Matthews, J;Pelletier, J
RNA解旋酶是真核生物RNA代谢中最大的一类酶。DEXID/H-box推定的RNA解旋酶形成解旋酶超家族II，其成员由7个高度保守的氨基酸基序定义，使得所选成员的特异性靶向成为具有挑战性的药理学问题。翻译起始因子eIF 4A是典型的DEAD盒RNA解旋酶，其与eIF 4 B和eIF 4 H结合并作为eIF 4F的亚基工作以制备用于核糖体结合的mRNA模板，可能通过解旋邻近5' m（7）GpppN帽结构的二级结构。我们报告了真核生物翻译起始的小分子抑制剂的鉴定和表征，其通过刺激eIF 4A相关活性以不寻常的方式起作用。我们的研究结果表明，eIF 4A解旋酶活性的适当控制是必要的有效的核糖体结合，并证明了选择性靶向DEAD盒RNA解旋酶与小分子的可行性。
RNA helicases are the largest group of enzymes in eukaryotic RNA metabolism. The DEXID/H-box putative RNA helicases form the helicase superfamily II, whose members are defined by seven highly conserved amino acid motifs, making specific targeting of selected members a challenging pharmacological problem. The translation initiation factor elF4A is the prototypical DEAD-box RNA helicase that works in conjunction with elF4B and eIF4H and as a subunit of elF4F to prepare the mRNA template for ribosome binding, possibly by unwinding the secondary structure proximal to the 5' m(7)GpppN cap structure. We report the identification and characterization of a small molecule inhibitor of eukaryotic translation initiation that acts in an unusual manner by stimulating elF4A-associated activities. Our results suggest that proper control of elF4A helicase activity is necessary for efficient ribosome binding and demonstrate the feasibility of selectively targeting DEAD-box RNA helicases with small molecules.