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

Chenxiao Jiang; Yegen Tang; Lulu Ding; Renke Tan; Xiaojing Li; Junyan Lu; Jing Jiang; Zhaomeng Cui; Zhewei Tang; Wei Li; Zhangjun Cao; Tilman Schneider-Poetsch; Wei Jiang; Cheng Luo; Yu Ding; Jianwei Liu; Yongjun Dang

doi:10.1016/j.chembiol.2019.07.010

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

Cell Chem Biol. 2019 Oct 17;26(10):1417-1426.e5. doi: 10.1016/j.chembiol.2019.07.010. Epub 2019 Aug 8.

Authors

Chenxiao Jiang¹, Yegen Tang², Lulu Ding³, Renke Tan⁴, Xiaojing Li⁴, Junyan Lu⁵, Jing Jiang⁶, Zhaomeng Cui⁴, Zhewei Tang⁴, Wei Li⁷, Zhangjun Cao⁶, Tilman Schneider-Poetsch⁸, Wei Jiang⁴, Cheng Luo⁹, Yu Ding¹⁰, Jianwei Liu¹¹, Yongjun Dang¹²

Affiliations

¹ Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
² Department of Chemistry, Fudan University, Shanghai 200032, China.
³ School of Life Science, Fudan University, Shanghai 200438, China.
⁴ Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
⁵ European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
⁶ College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai, 200051, China.
⁷ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
⁸ Chemical Genetics Laboratory, RIKEN, Wako, Saitama, 351-0198, Japan.
⁹ Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
¹⁰ School of Life Science, Fudan University, Shanghai 200438, China. Electronic address: yuding@fudan.edu.cn.
¹¹ Department of Chemistry, Fudan University, Shanghai 200032, China. Electronic address: jianweiliu@fudan.edu.cn.
¹² Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China. Electronic address: yongjundang@fudan.edu.cn.

PMID: 31402318
DOI: 10.1016/j.chembiol.2019.07.010

Abstract

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.

Keywords: DEAD-box protein; eIF4AI; sanguinarine; target validation; translation initiation.

MeSH terms

Animals
Benzophenanthridines / chemistry
Benzophenanthridines / pharmacology*
Biocatalysis
Cell Line
Dose-Response Relationship, Drug
Eukaryotic Initiation Factor-4A / antagonists & inhibitors*
Eukaryotic Initiation Factor-4A / metabolism
Female
Humans
Isoquinolines / chemistry
Isoquinolines / pharmacology*
Male
Mice
Models, Molecular
Molecular Conformation
Structure-Activity Relationship

Substances

Benzophenanthridines
EIF4A1 protein, human
Isoquinolines
sanguinarine
Eukaryotic Initiation Factor-4A