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Target Identification and Mechanistic Characterization of Indole Terpenoid Mimics: Proper Spindle Microtubule Assembly Is Essential for Cdh1-Mediated Proteolysis of CENP-A

文献类型：期刊论文

作者Peng, Yan8; Zhang, Yumeng8; Fang, Ruan7,8; Jiang, Hao6; Lan, Gongcai8; Xu, Zhou7; Liu, Yajie8; Nie, Zhaoyang4,5,7; Ren, Lu7; Wang, Fengcan8
刊名ADVANCED SCIENCE
出版日期2024-06-14
页码14
关键词Cdh1 CENP-A regulation colchicine-binding site inhibitor indole terpenoid target identification
DOI10.1002/advs.202305593
通讯作者Zhang, Wei-Dong(wdzhangy@hotmail.com) ; Luo, Cheng(cluo@simm.ac.cn) ; Li, Ang(ali@sioc.ac.cn) ; He, Weiwei(heweiwei@ecust.edu.cn)
英文摘要Centromere protein A (CENP-A), a histone H3 variant specific to centromeres, is crucial for kinetochore positioning and chromosome segregation. However, its regulatory mechanism in human cells remains incompletely understood. A structure-activity relationship (SAR) study of the cell-cycle-arresting indole terpenoid mimic JP18 leads to the discovery of two more potent analogs, (+)-6-Br-JP18 and (+)-6-Cl-JP18. Tubulin is identified as a potential cellular target of these halogenated analogs by using the drug affinity responsive target stability (DARTS) based method. X-ray crystallography analysis reveals that both molecules bind to the colchicine-binding site of beta-tubulin. Treatment of human cells with microtubule-targeting agents (MTAs), including these two compounds, results in CENP-A accumulation by destabilizing Cdh1, a co-activator of the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase. This study establishes a link between microtubule dynamics and CENP-A accumulation using small-molecule tools and highlights the role of Cdh1 in CENP-A proteolysis. The indole terpenoid mimic (+)-6-Br-JP18 disrupts spindle microtubule assembly by targeting the colchicine-binding site of beta-tubulin, which leads to downregulation of Cdh1, a co-activator of the APC/C E3 ubiquitin ligase, and accumulation of its substrate CENP-A in human cells. image
WOS关键词CELL-CYCLE ; TUBULIN ; PHOSPHORYLATION ; UBIQUITYLATION ; DEPOSITION ; COLCHICINE ; PROTEIN ; DESIGN ; MARKER
资助项目National Natural Science Foundation of China ; Institutes of Biomedical Science (IBS) at Fudan University ; Chinese Academy of Sciences[YSBR-095] ; Chinese Academy of Sciences[XBZG-ZDSYS-202303] ; Chinese Academy of Sciences[121731KYSB20190039] ; Chinese Academy of Sciences[QYZDB-SSW-SLH040] ; Science and Technology Commission of Shanghai Municipality[JCYJ-SHFY-2022-005] ; Science and Technology Commission of Shanghai Municipality[20430713400] ; New Cornerstone Science Foundation for the XplorerPrize ; [21931014] ; [U2002221] ; [21572064] ; [81502956]
WOS研究方向Chemistry ; Science & Technology - Other Topics ; Materials Science
语种英语
WOS记录号WOS:001247125700001
出版者WILEY
源URL[http://119.78.100.183/handle/2S10ELR8/311419]  
专题新药研究国家重点实验室
通讯作者Zhang, Wei-Dong; Luo, Cheng; Li, Ang; He, Weiwei
作者单位1.Second Mil Med Univ, Sch Pharm, Dept Phytochem, Shanghai 200433, Peoples R China
2.Anhui Univ, Inst Phys Sci & Informat Technol, Hefei 230601, Peoples R China
3.Qinghai Univ, State Key Lab Plateau Ecol & Agr, Xining 810016, Peoples R China
4.Zhengzhou Univ, Coll Chem, Zhengzhou 450001, Peoples R China
5.Zhengzhou Univ, Henan Inst Adv Technol, Zhengzhou 450001, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China
7.Chinese Acad Sci, Univ Chinese Acad Sci, Shanghai Inst Organ Chem, State Key Lab Chem Biol, Shanghai 200032, Peoples R China
8.East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China
推荐引用方式
GB/T 7714		 Peng, Yan,Zhang, Yumeng,Fang, Ruan,et al. Target Identification and Mechanistic Characterization of Indole Terpenoid Mimics: Proper Spindle Microtubule Assembly Is Essential for Cdh1-Mediated Proteolysis of CENP-A[J]. ADVANCED SCIENCE,2024:14.
APA Peng, Yan.,Zhang, Yumeng.,Fang, Ruan.,Jiang, Hao.,Lan, Gongcai.,...&He, Weiwei.(2024).Target Identification and Mechanistic Characterization of Indole Terpenoid Mimics: Proper Spindle Microtubule Assembly Is Essential for Cdh1-Mediated Proteolysis of CENP-A.ADVANCED SCIENCE,14.
MLA Peng, Yan,et al."Target Identification and Mechanistic Characterization of Indole Terpenoid Mimics: Proper Spindle Microtubule Assembly Is Essential for Cdh1-Mediated Proteolysis of CENP-A".ADVANCED SCIENCE (2024):14.

入库方式： OAI收割

来源：上海药物研究所

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