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Molecular basis for allosteric agonism and G protein subtype selectivity of galanin receptors

文献类型：期刊论文

作者Duan, Jia12,13; Shen, Dan-Dan10,11; Zhao, Tingting8,9; Guo, Shimeng8,9; He, Xinheng12,13; Yin, Wanchao13; Xu, Peiyu13; Ji, Yujie12,13; Chen, Li-Nan10,11; Liu, Jinyu8,9
刊名NATURE COMMUNICATIONS
出版日期2022-03-15
卷号13期号:1页码:13
DOI10.1038/s41467-022-29072-3
通讯作者Xu, H. Eric(eric.xu@simm.ac.cn) ; Zhang, Yan(zhang_yan@zju.edu.cn) ; Xie, Xin(xxie@simm.ac.cn) ; Jiang, Yi(yijiang@simm.ac.cn)
英文摘要The basis for the diverse peptide-binding modes and the G protein selectivity of peptide GPCRs remains elusive. Here, the authors offer a structural basis for allosteric-like agonism and G protein selectivity of a neuropeptide GPCR, galanin receptor. Peptide hormones and neuropeptides are complex signaling molecules that predominately function through G protein-coupled receptors (GPCRs). Two unanswered questions remaining in the field of peptide-GPCR signaling systems pertain to the basis for the diverse binding modes of peptide ligands and the specificity of G protein coupling. Here, we report the structures of a neuropeptide, galanin, bound to its receptors, GAL1R and GAL2R, in complex with their primary G protein subtypes G(i) and G(q), respectively. The structures reveal a unique binding pose of galanin, which almost 'lays flat' on the top of the receptor transmembrane domain pocket in an alpha-helical conformation, and acts as an 'allosteric-like' agonist via a distinct signal transduction cascade. The structures also uncover the important features of intracellular loop 2 (ICL2) that mediate specific interactions with G(q), thus determining the selective coupling of G(q) to GAL2R. ICL2 replacement in G(i)-coupled GAL1R, mu OR, 5-HT1AR, and G(s)-coupled beta(2)AR and D1R with that of GAL2R promotes G(q) coupling of these receptors, highlighting the dominant roles of ICL2 in G(q) selectivity. Together our results provide insights into peptide ligand recognition and allosteric activation of galanin receptors and uncover a general structural element for G(q) coupling selectivity.
WOS关键词BINDING ; ASSAY ; DETERMINANTS ; CONFORMATION ; MUTAGENESIS ; LIGANDS ; CLONING ; TOOLS ; GALR1 ; SITE
资助项目National Natural Science Foundation[32171187] ; National Natural Science Foundation[82121005] ; National Natural Science Foundation[81730099] ; National Natural Science Foundation[81922071] ; National Natural Science Foundation[32130022] ; Ministry of Science and Technology (China)[2018YFA0507002] ; Ministry of Science and Technology (China)[2019YFA0508800] ; Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; Shanghai Municipal Science and Technology Major Project ; CAS Strategic Priority Research Program[XDB37030103] ; Shanghai Municipal Science and Technology Commission Grant[20S11903200] ; Zhejiang Province Science Fund for Distinguished Young Scholars[LR19H310001] ; MOE Frontier Science Center for Brain Science & Brain-Machine Integration, Zhejiang University ; Science and Technology Commission of Shanghai Municipal[20431900100] ; Jack Ma Foundation[2020-CMKYGG-05] ; Shanghai Sailing Program[19YF1457600] ; The Youth Innovation Promotion Association of Chinese Academy of Science[2018319]
WOS研究方向Science & Technology - Other Topics
语种英语
出版者NATURE PORTFOLIO
WOS记录号WOS:000804856300015
源URL[http://119.78.100.183/handle/2S10ELR8/301413]  
专题新药研究国家重点实验室
通讯作者Xu, H. Eric; Zhang, Yan; Xie, Xin; Jiang, Yi
作者单位1.Lingang Lab, Shanghai 200031, Peoples R China
2.Univ Chinese Acad Sci, Sch Pharmaceut Sci & Technol, Hangzhou Inst Adv Study, Hangzhou 310024, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
4.Key Lab Immun & Inflammatory Dis Zhejiang Prov, Hangzhou, Zhejiang, Peoples R China
5.Zhejiang Univ, MOE Frontier Sci Ctr Brain Res & Brain Machine In, Sch Med, Hangzhou, Zhejiang, Peoples R China
6.Zhejiang Univ, Liangzhu Lab, Med Ctr, Hangzhou, Zhejiang, Peoples R China
7.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
8.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
9.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210046, Peoples R China
10.Zhejiang Univ, Sch Med, Dept Pathol, Sir Run Run Shaw Hosp, Hangzhou, Zhejiang, Peoples R China
推荐引用方式
GB/T 7714		 Duan, Jia,Shen, Dan-Dan,Zhao, Tingting,et al. Molecular basis for allosteric agonism and G protein subtype selectivity of galanin receptors[J]. NATURE COMMUNICATIONS,2022,13(1):13.
APA Duan, Jia.,Shen, Dan-Dan.,Zhao, Tingting.,Guo, Shimeng.,He, Xinheng.,...&Jiang, Yi.(2022).Molecular basis for allosteric agonism and G protein subtype selectivity of galanin receptors.NATURE COMMUNICATIONS,13(1),13.
MLA Duan, Jia,et al."Molecular basis for allosteric agonism and G protein subtype selectivity of galanin receptors".NATURE COMMUNICATIONS 13.1(2022):13.

入库方式： OAI收割

来源：上海药物研究所

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