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  2. 上海药物研究所
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  4. 新药研究国家重点实验室
Loops Mediate Agonist-Induced Activation of the Stimulator of Interferon Genes Protein

文献类型：期刊论文

作者Li, Rui3,4; Chen, Lin3; He, Xinheng2,3; Cao, Duanhua3; Zhang, Zehong3; Jiang, Hualiang3,4; Chen, Kaixian2,3,4; Cheng, Xi1,2,3
刊名JOURNAL OF CHEMICAL INFORMATION AND MODELING
出版日期2023-10-13
页码9
ISSN号1549-9596
DOI10.1021/acs.jcim.3c00984
通讯作者Jiang, Hualiang(hljiang@simm.ac.cn) ; Chen, Kaixian(kxchen@simm.ac.cn) ; Cheng, Xi(xicheng@simm.ac.cn)
英文摘要The stimulator of interferon genes (STING) is an important therapeutic target for cancer diseases. The activated STING recruits downstream tank-binding kinase 1 (TBK1) to trigger several important immune responses. However, the molecular mechanism of how agonist molecules mediate the STING-TBK1 interactions remains elusive. Here, we performed molecular dynamics simulations to capture the conformational changes of STING and TBK1 upon agonist binding. Our simulations revealed that multiple helices (alpha 5-alpha 7) and especially three loops (loop 6, loop 8, and C-terminal tail) of STING participated in the allosteric mediation of the STING-TBK1 interactions. Consistent results were also observed in the simulations of the constitutive activating mutant of STING (R284S). We further identified alpha 5 as a key region in this agonist-induced activation mechanism of STING. Free-energy perturbation calculations of multiple STING agonists demonstrated that an alkynyl group targeting alpha 5 is a determinant for agonist activities. These results not only offer deeper insights into the agonist-induced allosteric mediation of STING-TKB1 interactions but also provide a guidance for future drug development of this important therapeutic target.
WOS关键词PARTICLE-MESH EWALD ; SIDE-CHAIN ; AMBER ; PARAMETERS ; QUALITY
资助项目Shanghai Municipal Science and Technology Major Project ; Lingang Laboratory grant[LG202102-01-01] ; Fund of Youth Innovation Promotion Association[2022077] ; National Key Research and Development Program of China[2021YFA1301900]
WOS研究方向Pharmacology & Pharmacy ; Chemistry ; Computer Science
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:001092912900001
源URL[http://119.78.100.183/handle/2S10ELR8/307730]  
专题新药研究国家重点实验室
通讯作者Jiang, Hualiang; Chen, Kaixian; Cheng, Xi
作者单位1.Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
2.Univ Chinese Acad Sci, Beijing 101408, Peoples R China
3.Shanghai Inst Mat Med, Chinese Acad Sci, State Key Lab Drug Res, Shanghai 201203, Peoples R China
4.China Pharmaceut Univ, Sch Pharm, 639 Longmian Rd, Nanjing 211198, Peoples R China
推荐引用方式
GB/T 7714		 Li, Rui,Chen, Lin,He, Xinheng,et al. Loops Mediate Agonist-Induced Activation of the Stimulator of Interferon Genes Protein[J]. JOURNAL OF CHEMICAL INFORMATION AND MODELING,2023:9.
APA Li, Rui.,Chen, Lin.,He, Xinheng.,Cao, Duanhua.,Zhang, Zehong.,...&Cheng, Xi.(2023).Loops Mediate Agonist-Induced Activation of the Stimulator of Interferon Genes Protein.JOURNAL OF CHEMICAL INFORMATION AND MODELING,9.
MLA Li, Rui,et al."Loops Mediate Agonist-Induced Activation of the Stimulator of Interferon Genes Protein".JOURNAL OF CHEMICAL INFORMATION AND MODELING (2023):9.

入库方式： OAI收割

来源：上海药物研究所

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