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

作　　者：Jia Guo Yun-Li Zhou Yixin Yang Shimeng Guo Erli You Xin Xie Yi Jiang Chunyou Mao H.Eric Xu Yan Zhan 

机构地区：[1]Department of Pharmacology and Department of Pathology of Sir Run Run Shaw Hospital,Zhejiang University School of Medicine,Hangzhou,Zhejang,China [2]Liangzhu Laboratory,Zhejiang University,Hangzhou,Zhejiang,China [3]Department of General Surgery,Sir Run Run Shaw Hospital,Zhejiang University School of Medicine,Hangzhou,Zhejiang,China [4]Center for Structural Pharmacology and Therapeutics Development,Sir Run Run Shaw Hospital,Zhejiang University School of Medicine,Hangzhou,Zhejiang,China [5]CAS Key Laboratory of Receptor Research,Center for Structure and Function of Drug Targets,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,China [6]University of Chinese Academy of Sciences,Bejing,China [7]Lingang Laboratory,Shanghai,China [8]Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment,Zhejiang University,Hangzhou,Zhejiang,China [9]MOE Frontier Science Center for Brain Research and Brain-Machine Integration,Zhejiang University School of Medicine,Hangzhou,Zhejiang,China

出　　处：《Cell Research》2024年第10期725-734,共10页细胞研究（英文版）

基　　金：the National Natural Science Foundation of China(32371249/32100959/82322070 to C.M.,92353303/32141004 to Y.Z.,32171187 to Y.J.82121005 to YJ.and H.E.X.,32130022 to H.E.X.);the Ministry of Science and Technology(2019YFA050880 to Y.Z.);the"Pioneer"and"Leading Goose"R&D Program of Zhejiang(2024C03147 to Y.Z.);the Key R&D Projects of Zhejiang Province(2021C03039 to Y.Z.);the Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang(2020R01006 to Y.Z.);the Zhejiang Province Natural Science Fund for Excellent Young Scholars(LR22C050002 to C.M.);the Ministry of Science and Technology(2023YFC2306800 to C.M.);the Lingang Laboratory(LG-GG-202204-01 to YJ.and H.E.X.);CAS Strategic Priority Research Program(XDB37030103 to H.E.X.);Shanghai Municipal Science and Technology Major Project(2019SHZDZX02 to H.E.X.);Shanghai Municipal Science and Technology Major Project(H.E.X.);the Fundamental Research Funds for the Central Universities(226-2022-00205 to Y.Z.).

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 Gg and G;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 formingβ-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 Ga 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.

关 键 词：ACTIVATION COUPLING ROTATION 

分 类 号：O62[理学—有机化学]