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Targeting the N Terminus of eIF4AI for Inhibition of Its Catalytic Recycling

文献类型：期刊论文

作者Jiang, Chenxiao2,8; Tang, Yegen3; Ding, Lulu1; Tan, Renke2; Li, Xiaojing2; Lu, Junyan5; Jiang, Jing4; Cui, Zhaomeng2; Tang, Zhewei2; Li, Wei6
刊名CELL CHEMICAL BIOLOGY
出版日期2019-10-17
卷号26期号:10页码:1417-+
ISSN号2451-9448
DOI10.1016/j.chembiol.2019.07.010
通讯作者Ding, Yu(yuding@fudan.edu.cn) ; Liu, Jianwei(jianweiliu@fudan.edu.cn) ; Dang, Yongjun(yongjundang@fudan.edu.cn)
英文摘要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.
WOS关键词BENZOPHENANTHRIDINE ALKALOID SANGUINARINE ; EUKARYOTIC TRANSLATION INITIATION ; BOX PROTEIN EIF4A ; MESSENGER-RNA ; CRYSTAL-STRUCTURE ; FACTOR 4A ; KAPPA-B ; ATPASE ; ACTIVATION ; EXPRESSION
资助项目National Natural Science Foundation of China[31270830] ; National Natural Science Foundation of China[21572038] ; National Natural Science Foundation of China[81502394] ; National Natural Science Foundation of China[31470764] ; National Natural Science Foundation of China[91527305] ; Natural Science Foundation of Shanghai[19ZR1405200] ; Development Fund for Shanghai Talents ; Fund of State Key Laboratory of Bioorganic and Natural Products Chemistry ; Fund of State Key Laboratory of Drug Research ; Chinese Academy of Science[SIMM1601KF-08]
WOS研究方向Biochemistry & Molecular Biology
语种英语
出版者CELL PRESS
WOS记录号WOS:000490904200010
源URL[http://119.78.100.183/handle/2S10ELR8/282746]  
专题新药研究国家重点实验室
通讯作者Ding, Yu; Liu, Jianwei; Dang, Yongjun
作者单位1.Fudan Univ, Sch Life Sci, Shanghai 200438, Peoples R China
2.Fudan Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, Key Lab Metab & Mol Med,Minist Educ, Shanghai 200032, Peoples R China
3.Fudan Univ, Dept Chem, Shanghai 200032, Peoples R China
4.Donghua Univ, Coll Chem Chem Engn & Biotechnol, Shanghai 200051, Peoples R China
5.EMBL, Heidelberg, Germany
6.China Pharmaceut Univ, Dept Med Chem, Nanjing 210009, Jiangsu, Peoples R China
7.RIKEN, Chem Genet Lab, Wako, Saitama 3510198, Japan
8.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Jiang, Chenxiao,Tang, Yegen,Ding, Lulu,et al. Targeting the N Terminus of eIF4AI for Inhibition of Its Catalytic Recycling[J]. CELL CHEMICAL BIOLOGY,2019,26(10):1417-+.
APA Jiang, Chenxiao.,Tang, Yegen.,Ding, Lulu.,Tan, Renke.,Li, Xiaojing.,...&Dang, Yongjun.(2019).Targeting the N Terminus of eIF4AI for Inhibition of Its Catalytic Recycling.CELL CHEMICAL BIOLOGY,26(10),1417-+.
MLA Jiang, Chenxiao,et al."Targeting the N Terminus of eIF4AI for Inhibition of Its Catalytic Recycling".CELL CHEMICAL BIOLOGY 26.10(2019):1417-+.

入库方式： OAI收割

来源：上海药物研究所

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