Targeting the N Terminus of eIF4AI for Inhibition of Its Catalytic Recycling
Targeting the N Terminus of eIF4AI for Inhibition of Its Catalytic Recycling
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靶向 eIF4AI 的 N 末端以抑制其催化回收
DOI：
10.1016/j.chembiol.2019.07.010
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发表时间：
2019
影响因子：
8.6
通讯作者：
Dang Yongjun
中科院分区：
文献类型：
--
作者：
Jiang Chenxiao;Tang Yegen;Ding Lulu;Tan Renke;Li Xiaojing;Lu Junyan;Jiang Jing;Cui Zhaomeng;Tang Zhewei;Li Wei;Cao Zhangjun;Schneider Poetsch Tilman;Jiang Wei;Luo Cheng;Ding Yu;Liu Jianwei;Dang Yongjun
DEAD-box ATP-dependent helicases (DEAH/D) are a family of conserved genes predominantly involved in gene expression regulation and RNA processing. As its prototype, eIF4AI is an essential component of the protein translation initiation complex. Utilizing a screening system based on wild-type eIF4AI and its L243G mutant with a changed linker domain, we discovered an eIF4AI inhibitor, sanguinarine (SAN) and used it to study the catalytic mechanism of eIF4AI. Herein, we describe the crystal structure of the eIF4AI-inhibitor complex and demonstrate that the binding site displays certain specificity, which can provide the basis for drug design to target eIF4AI. We report that except for competitive inhibition SAN's possible mechanism of action involves interference with eIF4AI catalytic cycling process by hindering the formation of the closed conformation of eIF4AI. In addition, our results highlight a new targetable site on eIF4AI and confirm eIF4AI as a viable pharmacological target.
