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Two distinct domains of the glucagon-like peptide-1 receptor control peptide-mediated biased agonism

文献类型：期刊论文

作者Lei, Saifei2,3,5; Clydesdale, Lachlan1; Dai, Antao2,3; Cai, Xiaoqing2,3; Feng, Yang2,3; Yang, Dehua2,3; Liang, Yi-Lynn1; Koole, Cassandra1; Zhao, Peishen1; Coudrat, Thomas1
刊名JOURNAL OF BIOLOGICAL CHEMISTRY
出版日期2018-06-15
卷号293期号:24页码:9370-9387
关键词G protein-coupled receptor (GPCR) glucagon receptor structure-function cell signaling site-directed mutagenesis biased agonism GLP-1 receptor glucagon-like peptide-1 class B peptide hormone ERK kinase arrestin transmembrane domain
ISSN号0021-9258
DOI10.1074/jbc.RA118.003278
文献子类Article
英文摘要G protein-coupled receptors (GPCRs) can be differentially activated by ligands to generate multiple and distinct downstream signaling profiles, a phenomenon termed biased agonism. The glucagon-like peptide-1 receptor (GLP-1R) is a class B GPCR and a key drug target for managing metabolic disorders; however, its peptide agonists display biased signaling that affects their relative efficacies. In this study, we combined mutagenesis experiments and mapping of surface mutations onto recently described GLP-1R structures, which revealed two major domains in the GLP-1/GLP-1R/G(s) protein active structure that are differentially important for both receptor quiescence and ligand-specific initiation and propagation of biased agonism. Changes to the conformation of transmembrane helix (TM) 5 and TM 6 and reordering of extracellular loop 2 were essential for the propagation of signaling linked to cAMP formation and intracellular calcium mobilization, whereas ordering and packing of residues in TMs 1 and 7 were critical for extracellular signal-regulated kinase 1/2 (pERK) activity. On the basis of these findings, we propose a model of distinct peptide-receptor interactions that selectively control how these different signaling pathways are engaged. This work provides important structural insight into class B GPCR activation and biased agonism.
WOS关键词PROTEIN-COUPLED RECEPTORS ; CRYO-EM STRUCTURE ; CLASS-B GPCRS ; GLP-1 RECEPTOR ; TRANSMEMBRANE DOMAIN ; LIGAND-BINDING ; N-TERMINUS ; ACTIVATION ; COMPLEX ; MECHANISM
资助项目National Health and Medical Research Council of Australia[1061044] ; National Health and Medical Research Council of Australia[1065410] ; National Health and Medical Research Council of Australia[1126857] ; National Health and Medical Research Council[1055134] ; Shanghai Science and Technology Development Fund[15DZ2291600] ; National Natural Science Foundation of China[81573479] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020347] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12040308] ; Chinese Academy of Sciences[00000000]
WOS研究方向Biochemistry & Molecular Biology
语种英语
WOS记录号WOS:000435441400022
出版者AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
源URL[http://119.78.100.183/handle/2S10ELR8/279703]  
专题国家新药筛选中心
通讯作者Wang, Ming-Wei; Wootten, Denise; Sexton, Patrick M.
作者单位1.Monash Univ, Monash Inst Pharmaceut Sci, Drug Discovery Biol, Parkville, Vic 3052, Australia;
2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China;
3.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China;
4.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China
5.Univ Chinese Acad Sci, Sch Pharm, 19A Yuquan Rd, Beijing 100049, Peoples R China;
推荐引用方式
GB/T 7714		 Lei, Saifei,Clydesdale, Lachlan,Dai, Antao,et al. Two distinct domains of the glucagon-like peptide-1 receptor control peptide-mediated biased agonism[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2018,293(24):9370-9387.
APA Lei, Saifei.,Clydesdale, Lachlan.,Dai, Antao.,Cai, Xiaoqing.,Feng, Yang.,...&Sexton, Patrick M..(2018).Two distinct domains of the glucagon-like peptide-1 receptor control peptide-mediated biased agonism.JOURNAL OF BIOLOGICAL CHEMISTRY,293(24),9370-9387.
MLA Lei, Saifei,et al."Two distinct domains of the glucagon-like peptide-1 receptor control peptide-mediated biased agonism".JOURNAL OF BIOLOGICAL CHEMISTRY 293.24(2018):9370-9387.

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来源：上海药物研究所

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