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| Cryo-electron microscopy structure of the glucagon receptor with a dual-agonist peptide | |
Chang, Rulue1; Zhang, Xin2; Qiao, Anna3,4; Dai, Antao3,5; Belousoff, Matthew J.2; Tan, Qiuxiang3,4; Shao, Lijun3,4,6  ; Zhong, Li3,4; Lin, Guangyao3,4,6; Liang, Yi-Lynn2; Ma, Limin3; Han, Shuo3; Yang, Dehua3,5; Danev, Radostin7; Wang, Ming-Wei1,3,4,5,6; Wootten, Denise2; Wu, Beili3,4,6; Sexton, Patrick M.2
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| 2020-07-10 | |
| 发表期刊 | JOURNAL OF BIOLOGICAL CHEMISTRY (IF:4.0[JCR-2023],4.4[5-Year]) |
| ISSN | 0021-9258 |
| EISSN | 1083-351X |
| 卷号 | 295期号:28页码:9313-9325 |
| 发表状态 | 已发表 |
| DOI | 10.1074/jbc.ra120.013793 |
| 摘要 | Unimolecular dual agonists of the glucagon (GCG) receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R) are a new class of drugs that are potentially superior to GLP-1R–specific agonists for the management of metabolic disease. The dual-agonist, peptide 15 (P15), is a glutamic acid 16 analog of GCG with GLP-1 peptide substitutions between amino acids 17 and 24 that has potency equivalent to those of the cognate peptide agonists at the GCGR and GLP-1R. Here, we have used cryo-EM to solve the structure of an active P15-GCGR-Gs complex and compared this structure to our recently published structure of the GCGR-Gs complex bound to GCG. This comparison revealed that P15 has a reduced interaction with the first extracellular loop (ECL1) and the top of transmembrane segment 1 (TM1) such that there is increased mobility of the GCGR extracellular domain and at the C terminus of the peptide compared with the GCG-bound receptor. We also observed a distinct conformation of ECL3 and could infer increased mobility of the far N-terminal His-1 residue in the P15-bound structure. These regions of conformational variance in the two peptide-bound GCGR structures were also regions that were distinct between GCGR structures and previously published peptide-bound structures of the GLP-1R, suggesting that greater conformational dynamics may contribute to the increased efficacy of P15 in activation of the GLP-1R compared with GCG. The variable domains in this receptor have previously been implicated in biased agonism at the GLP-1R and could result in altered signaling of P15 at the GCGR compared with GCG. © 2020 Chang et al. |
| 关键词 | Electron microscopy Medical imaging Electron microscopes Amino acids Bound structure Conformational dynamics Cryo-electron microscopy Extracellular domains Extracellular loops Glucagon-like peptide-1 Metabolic disease Transmembrane segments glucagon receptor glucagon-like peptide-1 receptor dual agonist cryo-electron microscopy single particle analysis structure-function structural biology peptide 15 (P15) metabolic disorder G protein?coupled receptor (GPCR) glucagon GLP-1 receptor |
| 收录类别 | EI ; SCI ; SCIE |
| 语种 | 英语 |
| 资助项目 | National Natural Science Foundation of China[81872915][31825010][81973373][81773792] |
| WOS研究方向 | Biochemistry & Molecular Biology |
| WOS类目 | Biochemistry & Molecular Biology |
| WOS记录号 | WOS:000552758600005 |
| 出版者 | American Society for Biochemistry and Molecular Biology Inc. |
| EI入藏号 | 20210109721266 |
| EI主题词 | Peptides |
| EI分类号 | 461.1 Biomedical Engineering ; 461.9 Biology ; 746 Imaging Techniques ; 804.1 Organic Compounds |
| WOS关键词 | CRYO-EM STRUCTURE ; BEAM-INDUCED MOTION ; GLP-1 RECEPTOR ; BIASED AGONISM ; RECOGNITION ; RESIDUES ; DYNAMICS ; OBESITY |
| 原始文献类型 | Journal article (JA) |
| 引用统计 | 正在获取...
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| 文献类型 | 期刊论文 |
| 条目标识符 | https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/251759 |
| 专题 | 生命科学与技术学院_博士生 生命科学与技术学院_特聘教授组_王明伟组 生命科学与技术学院_特聘教授组_吴蓓丽组 |
| 作者单位 | 1.School of Pharmacy, Shanghai Medical College, Fudan University, Shanghai, China; 2.Monash Institute of Pharmaceutical Sciences, Drug Discovery Biology, Monash University, Parkville; VIC, Australia; 3.CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; 4.University of Chinese Academy of Sciences, Beijing, China; 5.National Center for Drug Screening, Shanghai, China; 6.School of Life Science and Technology, ShanghaiTech University, Shanghai, China; 7.Graduate School of Medicine, University of Tokyo, Tokyo, Japan |
| 推荐引用方式 GB/T 7714 | Chang, Rulue,Zhang, Xin,Qiao, Anna,et al. Cryo-electron microscopy structure of the glucagon receptor with a dual-agonist peptide[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2020,295(28):9313-9325. |
| APA | Chang, Rulue.,Zhang, Xin.,Qiao, Anna.,Dai, Antao.,Belousoff, Matthew J..,...&Sexton, Patrick M..(2020).Cryo-electron microscopy structure of the glucagon receptor with a dual-agonist peptide.JOURNAL OF BIOLOGICAL CHEMISTRY,295(28),9313-9325. |
| MLA | Chang, Rulue,et al."Cryo-electron microscopy structure of the glucagon receptor with a dual-agonist peptide".JOURNAL OF BIOLOGICAL CHEMISTRY 295.28(2020):9313-9325. |
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