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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
GPCR activation and GRK2 assembly by a biased intracellular agonist

文献类型：期刊论文

作者Duan, Jia4,5,6; Liu, Heng4; Zhao, Fenghui7; Yuan, Qingning4; Ji, Yujie4,6; Cai, Xiaoqing7; He, Xinheng4,6; Li, Xinzhu4; Li, Junrui4; Wu, Kai4
刊名NATURE
出版日期2023-08-02
页码27
ISSN号0028-0836
DOI10.1038/s41586-023-06395-9
通讯作者Duan, Jia(duanjia@simm.ac.cn) ; Yang, Dehua(dhyang@simm.ac.cn) ; Xu, H. Eric(eric.xu@simm.ac.cn)
英文摘要Phosphorylation of G-protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) desensitizes G-protein signalling and promotes arrestin signalling, which is also modulated by biased ligands(1-6). The molecular assembly of GRKs on GPCRs and the basis of GRK-mediated biased signalling remain largely unknown owing to the weak GPCR-GRK interactions. Here we report the complex structure of neurotensin receptor 1 (NTSR1) bound to GRK2, Ga-q and the arrestin-biased ligand SBI-553(7). The density map reveals the arrangement of the intact GRK2 with the receptor, with the N-terminal helix of GRK2 docking into the open cytoplasmic pocket formed by the outward movement of the receptor transmembrane helix 6, analogous to the binding of the G protein to the receptor. SBI-553 binds at the interface between GRK2 and NTSR1 to enhance GRK2 binding. The binding mode of SBI-553 is compatible with arrestin binding but clashes with the binding of Ga-q protein, thus providing a mechanism for its arrestin-biased signalling capability. In sum, our structure provides a rational model for understanding the details of GPCR-GRK interactions and GRK2-mediated biased signalling.
WOS关键词ADRENERGIC-RECEPTOR KINASE ; BETA-GAMMA-SUBUNITS ; G-PROTEINS ; CRYSTAL-STRUCTURE ; COMPLEX ; NEUROTENSIN ; PHOSPHORYLATION ; RHODOPSIN ; ARRESTIN ; RECRUITMENT
资助项目CAS Strategic Priority Research Program[XDB37030103] ; Shanghai Municipal Science and Technology Major Project[LG-GG-202204-01] ; National Natural Science Foundation of China[32130022] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[82273961] ; National Natural Science Foundation of China[82273985] ; National Natural Science Foundation of China[82204474] ; National Key Ramp;D Program of China[2018YFA0507000] ; National Key Ramp;D Program of China[2022QNRC001] ; Young Elite Scientists Sponsorship Program by CAST[23YF1456800] ; Shanghai Sailing Program[2019SHZDZX02] ; Lingang Laboratory ; [2018YFA0507002]
WOS研究方向Science & Technology - Other Topics
语种英语
出版者NATURE PORTFOLIO
WOS记录号WOS:001045155200012
源URL[http://119.78.100.183/handle/2S10ELR8/306944]  
专题新药研究国家重点实验室
通讯作者Duan, Jia; Yang, Dehua; Xu, H. Eric
作者单位1.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
2.Res Ctr Deepsea Bioresources, Sanya, Hainan, Peoples R China
3.Lingang Lab, Shanghai, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
5.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan, Peoples R China
6.Univ Chinese Acad Sci, Beijing, Peoples R China
7.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Duan, Jia,Liu, Heng,Zhao, Fenghui,et al. GPCR activation and GRK2 assembly by a biased intracellular agonist[J]. NATURE,2023:27.
APA Duan, Jia.,Liu, Heng.,Zhao, Fenghui.,Yuan, Qingning.,Ji, Yujie.,...&Xu, H. Eric.(2023).GPCR activation and GRK2 assembly by a biased intracellular agonist.NATURE,27.
MLA Duan, Jia,et al."GPCR activation and GRK2 assembly by a biased intracellular agonist".NATURE (2023):27.

入库方式： OAI收割

来源：上海药物研究所

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