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Structural basis of tethered agonism and G protein coupling of protease-activated receptors

文献类型：期刊论文

作者Guo, Jia5,6,7,8,9,10; Zhou, Yun-Li9,10; Yang, Yixin9,10; Guo, Shimeng5; You, Erli5; Xie, Xin4,5; Jiang, Yi3; Mao, Chunyou2,6,7; Xu, H. Eric4,5; Zhang, Yan1,6,7,8,9,10
刊名CELL RESEARCH
出版日期2024-07-12
页码10
ISSN号1001-0602
DOI10.1038/s41422-024-00997-2
通讯作者Mao, Chunyou(maochunyou@zju.edu.cn) ; Xu, H. Eric(eric.xu@simm.ac.cn) ; Zhang, Yan(zhang_yan@zju.edu.cn)
英文摘要Protease-activated receptors (PARs) are a unique group within the G protein-coupled receptor superfamily, orchestrating cellular responses to extracellular proteases via enzymatic cleavage, which triggers intracellular signaling pathways. Protease-activated receptor 1 (PAR1) is a key member of this family and is recognized as a critical pharmacological target for managing thrombotic disorders. In this study, we present cryo-electron microscopy structures of PAR1 in its activated state, induced by its natural tethered agonist (TA), in complex with two distinct downstream proteins, the Gq and Gi heterotrimers, respectively. The TA peptide is positioned within a surface pocket, prompting PAR1 activation through notable conformational shifts. Contrary to the typical receptor activation that involves the outward movement of transmembrane helix 6 (TM6), PAR1 activation is characterized by the simultaneous downward shift of TM6 and TM7, coupled with the rotation of a group of aromatic residues. This results in the displacement of an intracellular anion, creating space for downstream G protein binding. Our findings delineate the TA recognition pattern and highlight a distinct role of the second extracellular loop in forming beta-sheets with TA within the PAR family, a feature not observed in other TA-activated receptors. Moreover, the nuanced differences in the interactions between intracellular loops 2/3 and the G alpha subunit of different G proteins are crucial for determining the specificity of G protein coupling. These insights contribute to our understanding of the ligand binding and activation mechanisms of PARs, illuminating the basis for PAR1's versatility in G protein coupling.
WOS关键词THROMBIN RECEPTOR ; MOLECULAR-CLONING ; CRYSTAL-STRUCTURE ; PAR1 ; VORAPAXAR ; SELECTIVITY ; DISCOVERY ; MECHANISM ; PLAYS ; ACID
资助项目National Natural Science Foundation of China[32371249] ; National Natural Science Foundation of China[32100959] ; National Natural Science Foundation of China[82322070] ; National Natural Science Foundation of China[92353303] ; National Natural Science Foundation of China[32141004] ; National Natural Science Foundation of China[32171187] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[32130022] ; Ministry of Science and Technology[2019YFA050880] ; Ministry of Science and Technology[2023YFC2306800] ; The Pioneer and Leading Goose R&D Program of Zhejiang[2024C03147] ; Key R&D Projects of Zhejiang Province[2021C03039] ; Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang[2020R01006] ; Zhejiang Province Natural Science Fund for Excellent Young Scholars[LR22C050002] ; Lingang Laboratory[LG-GG-202204-01] ; CAS Strategic Priority Research Program[XDB37030103] ; Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; Fundamental Research Funds for the Central Universities
WOS研究方向Cell Biology
语种英语
WOS记录号WOS:001270046500001
出版者SPRINGERNATURE
源URL[http://119.78.100.183/handle/2S10ELR8/312389]  
专题中国科学院上海药物研究所
通讯作者Mao, Chunyou; Xu, H. Eric; Zhang, Yan
作者单位1.Zhejiang Univ, MOE Frontier Sci Ctr Brain Res & Brain Machine Int, Sch Med, Hangzhou, Zhejiang, Peoples R China
2.Zhejiang Univ, Zhejiang Res & Dev Engn Lab Minimally Invas Techno, Hangzhou, Zhejiang, Peoples R China
3.Lingang Lab, Shanghai, Peoples R China
4.Univ Chinese Acad Sci, Beijing, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Struct & Funct Drug Targets, CAS Key Lab Receptor Res, Shanghai, Peoples R China
6.Zhejiang Univ, Sir Run Run Shaw Hosp, Sch Med, Ctr Struct Pharmacol & Therapeut Dev, Hangzhou, Zhejiang, Peoples R China
7.Zhejiang Univ, Sch Med, Sir Run Run Shaw Hosp, Dept Gen Surg, Hangzhou, Zhejiang, Peoples R China
8.Zhejiang Univ, Liangzhu Lab, Hangzhou, Zhejiang, Peoples R China
9.Zhejiang Univ, Sir Run Run Shaw Hosp, Sch Med, Dept Pathol, Hangzhou, Zhejiang, Peoples R China
10.Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Pharmacol, Sch Med, Hangzhou, Zhejiang, Peoples R China
推荐引用方式
GB/T 7714		 Guo, Jia,Zhou, Yun-Li,Yang, Yixin,et al. Structural basis of tethered agonism and G protein coupling of protease-activated receptors[J]. CELL RESEARCH,2024:10.
APA Guo, Jia.,Zhou, Yun-Li.,Yang, Yixin.,Guo, Shimeng.,You, Erli.,...&Zhang, Yan.(2024).Structural basis of tethered agonism and G protein coupling of protease-activated receptors.CELL RESEARCH,10.
MLA Guo, Jia,et al."Structural basis of tethered agonism and G protein coupling of protease-activated receptors".CELL RESEARCH (2024):10.

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来源：上海药物研究所

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