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Activation pathway of a G protein-coupled receptor uncovers conformational intermediates as targets for allosteric drug design

文献类型：期刊论文

作者Lu, Shaoyong2,3; He, Xinheng4,5; Yang, Zhao6; Chai, Zongtao7; Zhou, Shuhua6; Wang, Junyan6; Rehman, Ashfaq Ur3; Ni, Duan3; Pu, Jun1; Sun, Jinpeng6
刊名NATURE COMMUNICATIONS
出版日期2021-08-05
卷号12期号:1页码:15
ISSN号2041-1723
DOI10.1038/s41467-021-25020-9
通讯作者Lu, Shaoyong(lushaoyong@sjtu.edu.cn) ; Sun, Jinpeng(sunjinpeng@sdu.edu.cn) ; Zhang, Jian(jian.zhang@sjtu.edu.cn)
英文摘要G protein-coupled receptors (GPCRs) are the most common proteins targeted by approved drugs. A complete mechanistic elucidation of large-scale conformational transitions underlying the activation mechanisms of GPCRs is of critical importance for therapeutic drug development. Here, we apply a combined computational and experimental framework integrating extensive molecular dynamics simulations, Markov state models, site-directed mutagenesis, and conformational biosensors to investigate the conformational landscape of the angiotensin II (AngII) type 1 receptor (AT(1) receptor) - a prototypical class A GPCR-activation. Our findings suggest a synergistic transition mechanism for AT(1) receptor activation. A key intermediate state is identified in the activation pathway, which possesses a cryptic binding site within the intracellular region of the receptor. Mutation of this cryptic site prevents activation of the downstream G protein signaling and beta -arrestin-mediated pathways by the endogenous AngII octapeptide agonist, suggesting an allosteric regulatory mechanism. Together, these findings provide a deeper understanding of AT(1) receptor activation at an atomic level and suggest avenues for the design of allosteric AT(1) receptor modulators with a broad range of applications in GPCR biology, biophysics, and medicinal chemistry. G protein-coupled receptors (GPCRs) are a critical target in modern drug development across a wide range of indications. Here the authors provide a comprehensive characterization of a typical GPCR, the angiotensin II (AngII) type 1 receptor (AT1R), and provide insight into its activation mechanism that suggest avenues for the design of allosteric GPCR modulators.
WOS关键词CRYSTAL-STRUCTURE ; DYNAMIC PROCESS ; ANGIOTENSIN-II ; MECHANISM ; DISCOVERY ; REARRANGEMENT ; MODULATION ; MODELS ; SITES
资助项目National Natural Science Foundation of China[81925034] ; National Natural Science Foundation of China[22077082] ; National Natural Science Foundation of China[21778037] ; National Natural Science Foundation of China[91753117] ; National Natural Science Foundation of China[81721004] ; National Natural Science Foundation of China[91939301] ; Innovation Program of Shanghai Municipal Education Commission, China[2019-01-07-00-01-E00036] ; Shanghai Science and Technology Innovation, China[19431901600] ; Shanghai Health and Family Planning System Excellent Subject Leader and Excellent Young Medical Talents Training Program, China[2018BR12] ; CAMS Innovation Fund for Medical Sciences (CIFMS)[2019-I2M-5-051] ; Fundamental Research Funds for the Central Universities ; Center for high Performance Computing and System Simulation, Pilot National Laboratory for Marine Science and Technology (Qingdao) ; AlloStar(TM) platform of Nutshell Therapeutics
WOS研究方向Science & Technology - Other Topics
语种英语
出版者NATURE PORTFOLIO
WOS记录号WOS:000684407600010
源URL[http://119.78.100.183/handle/2S10ELR8/297967]  
专题中国科学院上海药物研究所
通讯作者Lu, Shaoyong; Sun, Jinpeng; Zhang, Jian
作者单位1.Shanghai Jiao Tong Univ, Dept Cardiol, Renji Hosp, Sch Med, Shanghai, Peoples R China
2.Ningxia Med Univ, Coll Pharm, Yinchuan, Ningxia Hui Aut, Peoples R China
3.Shanghai Jiao Tong Univ, State Key Lab Oncogenes & Related Genes, Key Lab Cell Differentiat & Apoptosis, Chinese Minist Educ,Sch Med, Shanghai, Peoples R China
4.Chinese Acad Sci, CAS Key Lab Receptor Res, Shanghai Inst Mat Med, Shanghai, Peoples R China
5.Univ Chinese Acad Sci, Beijing, Peoples R China
6.Shandong Univ, Dept Biochem & Mol Biol, Key Lab Expt Teratol, Chinese Minist Educ,Sch Med, Jinan, Shandong, Peoples R China
7.Second Mil Med Univ, Dept Hepat Surg 6, Eastern Hepatobiliary Surg Hosp, Shanghai, Peoples R China
8.Zhengzhou Univ, Sch Pharmaceut Sci, Zhengzhou, Peoples R China
推荐引用方式
GB/T 7714		 Lu, Shaoyong,He, Xinheng,Yang, Zhao,et al. Activation pathway of a G protein-coupled receptor uncovers conformational intermediates as targets for allosteric drug design[J]. NATURE COMMUNICATIONS,2021,12(1):15.
APA Lu, Shaoyong.,He, Xinheng.,Yang, Zhao.,Chai, Zongtao.,Zhou, Shuhua.,...&Zhang, Jian.(2021).Activation pathway of a G protein-coupled receptor uncovers conformational intermediates as targets for allosteric drug design.NATURE COMMUNICATIONS,12(1),15.
MLA Lu, Shaoyong,et al."Activation pathway of a G protein-coupled receptor uncovers conformational intermediates as targets for allosteric drug design".NATURE COMMUNICATIONS 12.1(2021):15.

入库方式： OAI收割

来源：上海药物研究所

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