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Structure basis for AA98 inhibition on the activation of endothelial cells mediated by CD146

文献类型：期刊论文

作者Chen, Xuehui1,5; Yan, Huiwen6; Liu, Dan5; Xu, Qingji4,5; Duan, Hongxia5; Feng, Jing5; Yan, Xiyun4,5; Xie, Can1,2,3
刊名ISCIENCE
出版日期2021-05-21
卷号24
DOI10.1016/j.isci.2021.102417
通讯作者Feng, Jing(fengjing@ibp.ac.cn) ; Yan, Xiyun(yanxy@ibp.ac.cn) ; Xie, Can(canxie@hmfl.ac.cn)
英文摘要CD146 is an adhesion molecule that plays important roles in angiogenesis, cancer metastasis, and immune response. It exists as a monomer or dimer on the cell surface. AA98 is a monoclonal antibody that binds to CD146, which abrogates the activation of CD146-mediated signaling pathways and shows inhibitory effects on tumor growth. However, how AA98 inhibits the function of CD146 remains unclear. Here, we describe a crystal structure of the CD146/AA98 Fab complex at a resolution of 2.8 angstrom. Monomeric CD146 is stabilized by AA98 Fab binding to the junction region of CD146 domains 4 and 5. A higher-affinity AA98 variant (here named HA98) was thus rationally designed. Better binding to CD146 and prominent inhibition on cell migration were achieved with HA98. Further experiments on xenografted melanoma in mice with HA98 revealed superior inhibitory effects on tumor growth to those of AA98, which suggested future applications of this antibody in cancer therapy.
WOS关键词ADHESION MOLECULE ; MONOCLONAL-ANTIBODY ; HUMAN-MELANOMA ; MCAM ; DIMERIZATION ; MUC18 ; RECEPTOR ; PROTEIN ; CANCER ; ANGIOGENESIS
资助项目National Natural Science Foundation of China[31770793] ; National Natural Science Foundation of China[31640001] ; National Natural Science Foundation of China[31370740] ; Hefei Institutes of Physical Science, Chinese Academy of Sciences[BJZX201901] ; Beijing Municipal Natural Science Foundation, China[7192123]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:000653990500031
出版者CELL PRESS
资助机构National Natural Science Foundation of China ; Hefei Institutes of Physical Science, Chinese Academy of Sciences ; Beijing Municipal Natural Science Foundation, China
源URL[http://ir.hfcas.ac.cn:8080/handle/334002/123750]  
专题中国科学院合肥物质科学研究院
通讯作者Feng, Jing; Yan, Xiyun; Xie, Can
作者单位1.Peking Univ, Sch Life Sci, State Key Lab Membrane Biol, Lab Mol Biophys, Beijing 100871, Peoples R China
2.Int Magnetobiol Frontier Res Ctr, Sci Isl, Hefei 230031, Peoples R China
3.Chinese Acad Sci, Hefei Inst Phys Sci, High Magnet Field Lab, Key Lab High Magnet Field & Ion Beam Phys Biol, Hefei 230031, Anhui, Peoples R China
4.Univ Chinese Acad Sci, Coll Life Sci, Beijing 100049, Peoples R China
5.Chinese Acad Sci, Inst Biophys, Key Lab Prot & Peptide Pharmaceut, Beijing 100101, Peoples R China
6.Chinese Acad Sci, Inst Biophys, Key Lab RNA Biol, Beijing 100101, Peoples R China
推荐引用方式
GB/T 7714		 Chen, Xuehui,Yan, Huiwen,Liu, Dan,et al. Structure basis for AA98 inhibition on the activation of endothelial cells mediated by CD146[J]. ISCIENCE,2021,24.
APA Chen, Xuehui.,Yan, Huiwen.,Liu, Dan.,Xu, Qingji.,Duan, Hongxia.,...&Xie, Can.(2021).Structure basis for AA98 inhibition on the activation of endothelial cells mediated by CD146.ISCIENCE,24.
MLA Chen, Xuehui,et al."Structure basis for AA98 inhibition on the activation of endothelial cells mediated by CD146".ISCIENCE 24(2021).

入库方式： OAI收割

来源：合肥物质科学研究院

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