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Structural insights into a shared mechanism of human STING activation by a potent agonist and an autoimmune disease-associated mutation

文献类型：期刊论文

作者Xie, Zuoquan1; Wang, Zhen2,3; Fan, Fengying2,3; Zhou, Jinpei4,5; Hu, Zhaoxue4,5; Wang, Qingxia2,3; Wang, Xiyuan1; Zeng, Qingzhong1,6; Zhang, Yan1; Qiu, Jiaxuan2,3,7
刊名CELL DISCOVERY
出版日期2022-12-13
卷号8期号:1页码:17
DOI10.1038/s41421-022-00481-4
通讯作者Zhang, Huibin(zhanghb80@cpu.edu.cn) ; Duan, Wenhu(whduan@simm.ac.cn) ; Yu, Xuekui(xkyu@simm.ac.cn) ; Geng, Meiyu(mygeng@simm.ac.cn)
英文摘要Stimulator of interferon gene (STING) is increasingly exploited for the potential in cancer immunotherapy, yet its mechanism of activation remains not fully understood. Herein, we designed a novel STING agonist, designated as HB3089 that exhibits robust and durable anti-tumor activity in tumor models across various cancer types. Cryo-EM analysis reveals that HB3089-bound human STING has structural changes similar to that of the STING mutant V147L, a constitutively activated mutant identified in patients with STING-associated vasculopathy with onset in infancy (SAVI). Both structures highlight the conformational changes of the transmembrane domain (TMD), but without the 180 & DEG;-rotation of the ligand binding domain (LBD) previously shown to be required for STING activation. Further structure-based functional analysis confirmed a new STING activation mode shared by the agonist and the SAVI-related mutation, in which the connector linking the LBD and the TMD senses the activation signal and controls the conformational changes of the LBD and the TMD for STING activation. Together, our findings lead to a new working model for STING activation and open a new avenue for the rationale design of STING-targeted therapies either for cancer or autoimmune disorders.
WOS关键词CYCLIC GMP-AMP ; DNA SENSOR ; DI-AMP ; ADAPTER ; DINUCLEOTIDE ; 2ND-MESSENGER ; TRANSLOCATION ; STIMULATOR ; REVEALS ; PATHWAY
资助项目Hundred Talents Program of Chinese Academy of Sciences ; Lingang Laboratory[LG202103-02-08] ; Shanghai Municipal Science andTechnology Major Project[TZX022021007] ; Natural Science Foundation of China for Innovation Research Group[81821005] ; National Natural Science Foundation of China[32000896] ; China Postdoctoral Science Foundation[2020M681427] ; Support of SANOFI Scholarship Program ; Collaborative Innovation Cluster Projectof Shanghai Municipal Commission of Health and Family Planning[2020CXJQ02] ; National Science & Technology Major Project Key NewDrug Creation and Manufacturing Program[2018ZX09711002-017]
WOS研究方向Cell Biology
语种英语
WOS记录号WOS:000898848100001
出版者SPRINGERNATURE
源URL[http://119.78.100.183/handle/2S10ELR8/304213]  
专题新药研究国家重点实验室
通讯作者Zhang, Huibin; Duan, Wenhu; Yu, Xuekui; Geng, Meiyu
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Cryo Electron Microscopy Res Ctr, Shanghai, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China
4.China Pharmaceut Univ, Dept Med Chem, Nanjing, Peoples R China
5.China Pharmaceut Univ, Ctr Drug Discovery, Nanjing, Peoples R China
6.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
7.Univ Chinese Acad Sci, Beijing, Peoples R China
8.Chinese Acad Sci, Shanghai Inst Mat Med, Small Mol Drug Res Ctr, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Xie, Zuoquan,Wang, Zhen,Fan, Fengying,et al. Structural insights into a shared mechanism of human STING activation by a potent agonist and an autoimmune disease-associated mutation[J]. CELL DISCOVERY,2022,8(1):17.
APA Xie, Zuoquan.,Wang, Zhen.,Fan, Fengying.,Zhou, Jinpei.,Hu, Zhaoxue.,...&Geng, Meiyu.(2022).Structural insights into a shared mechanism of human STING activation by a potent agonist and an autoimmune disease-associated mutation.CELL DISCOVERY,8(1),17.
MLA Xie, Zuoquan,et al."Structural insights into a shared mechanism of human STING activation by a potent agonist and an autoimmune disease-associated mutation".CELL DISCOVERY 8.1(2022):17.

入库方式： OAI收割

来源：上海药物研究所

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