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A Peptide Binder of E3 Ligase Adaptor SPOP Disrupts Oncogenic SPOP-Protein Interactions in Kidney Cancer Cells

文献类型：期刊论文

作者Wang, Zhen3,4; Zhang, Hao4,5; Chen, Baoen4; Ouyang, Sisheng4; Zheng, Tong4; Zhou, Ran4,5; Dong, Ze4; Huang, Yue4,6; Zhang, Tao4; Jiang, Hualiang2,4,5,6
刊名CHINESE JOURNAL OF CHEMISTRY
出版日期2020-12-31
页码274-280
关键词SPOP Protein‐ protein interaction Clear cell Renal Cell Carcinomas Crystal structure Peptide inhibitor
ISSN号1001-604X
DOI10.1002/cjoc.202000462
通讯作者Luo, Cheng(cluo@simm.ac.cn) ; Yang, Cai-Guang(yangcg@simm.ac.cn)
英文摘要Main observation and conclusion The E3 ligase adaptor SPOP, overexpressed in the nucleus but frequently dislocated into the cytoplasm in all clear cell Renal Cell Carcinomas (ccRCC), serves as a regulatory hub to promote kidney cancer through the ubiquitination and degradation of multiple downstream cancer proteins. Recently, our identification of a selective small-molecule inhibitor of the SPOP-phosphatase and tensin homolog (PTEN) interaction has demonstrated that the oncogenic SPOP-protein interaction would be a druggable target specific to ccRCC therapy. To our knowledge, this is the first time such a small-molecule inhibitor has been developed. Herein, we have identified a peptide binder for the SPOP-MATH domain that disrupts the oncogenic SPOP-protein interactions in kidney cancer cells. Computational design and biophysical characterization yielded peptide Pep38 that binds to the MATH domain of SPOP and competes on PTEN-binding to SPOP in vitro. The X-ray complex structure reveals that the peptide binder features the following combination: one, a mimic of the native peptide binder and two, an additional beta-strand motif in sequence, which could contribute to increased binding affinity. In order to improve cellular permeability, we fused Pep38 with the delivery peptide TAT to prepare peptide TAT38, which inhibits the endogenous substrate binding to SPOP and suppresses the proliferation of the ccRCC cells. Our identification of the peptide inhibitors for SPOP-protein interactions provides further validation that the oncogenic SPOP-signaling pathway in ccRCC could be a druggable target specifically applicable to the therapy of kidney cancers.
WOS关键词PROSTATE-CANCER ; DOCKING ; DEGRADATION ; MUTATIONS
资助项目National Natural Science Foundation of China[21725801] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[81430084] ; National Natural Science Foundation of China[21807103] ; National Key New Drug Creation and Manufacturing Program, Ministry of Science and Technology[2018ZX09711002] ; Science and Technology Commission of Shanghai Municipality[18YF1428500] ; Science and Technology Commission of Shanghai Municipality[18431907100] ; China Postdoctoral Science Foundation[2018M640434] ; China Postdoctoral Science Foundation[2017M621570] ; China Postdoctoral Science Foundation[2018M632187]
WOS研究方向Chemistry
语种英语
WOS记录号WOS:000603603500001
出版者WILEY-V C H VERLAG GMBH
源URL[http://119.78.100.183/handle/2S10ELR8/296021]  
专题新药研究国家重点实验室
通讯作者Luo, Cheng; Yang, Cai-Guang
作者单位1.Fudan Univ, Sch Life Sci, Shanghai 200433, Peoples R China
2.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 201210, Peoples R China
3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Jiangsu, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
6.UCAS, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Zhejiang, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Zhen,Zhang, Hao,Chen, Baoen,et al. A Peptide Binder of E3 Ligase Adaptor SPOP Disrupts Oncogenic SPOP-Protein Interactions in Kidney Cancer Cells[J]. CHINESE JOURNAL OF CHEMISTRY,2020:274-280.
APA Wang, Zhen.,Zhang, Hao.,Chen, Baoen.,Ouyang, Sisheng.,Zheng, Tong.,...&Yang, Cai-Guang.(2020).A Peptide Binder of E3 Ligase Adaptor SPOP Disrupts Oncogenic SPOP-Protein Interactions in Kidney Cancer Cells.CHINESE JOURNAL OF CHEMISTRY,274-280.
MLA Wang, Zhen,et al."A Peptide Binder of E3 Ligase Adaptor SPOP Disrupts Oncogenic SPOP-Protein Interactions in Kidney Cancer Cells".CHINESE JOURNAL OF CHEMISTRY (2020):274-280.

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来源：上海药物研究所

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