Cryo-electron microscopy structure of the glucagon receptor with a dual-agonist peptide
文献类型：期刊论文
| 作者 | Chang, Rulue2; Zhang, Xin3; Qiao, Anna4,5; Dai, Antao4,6; Belousoff, Matthew J.3; Tan, Qiuxiang4,5; Shao, Lijun4,5,7; Zhong, Li4,5; Lin, Guangyao4,5,7; Liang, Yi-Lynn3 |
| 刊名 | JOURNAL OF BIOLOGICAL CHEMISTRY
 |
| 出版日期 | 2020-07-10 |
| 卷号 | 295期号:28页码:9313-9325 |
| ISSN号 | 0021-9258 |
| 关键词 | 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 |
| DOI | 10.1074/jbc.RA120.013793 |
| 通讯作者 | Wang, Ming-Wei(mwwang@simm.ac.cn) ; Wootten, Denise(denise.wootten@monash.edu) ; Wu, Beili(beiliwu@simm.ac.cn) ; Sexton, Patrick M.(Patrick.sexton@monash.edu) |
| 英文摘要 | 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-G(s)complex and compared this structure to our recently published structure of the GCGR-G(s)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. |
| WOS关键词 | CRYO-EM STRUCTURE ; BEAM-INDUCED MOTION ; GLP-1 RECEPTOR ; BIASED AGONISM ; RECOGNITION ; RESIDUES ; DYNAMICS ; OBESITY |
| 资助项目 | National Natural Science Foundation of China[81872915] ; National Natural Science Foundation of China[31825010] ; National Natural Science Foundation of China[81973373] ; National Natural Science Foundation of China[81773792] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09735-001] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002-002-005] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002-001] ; National Key R&D Program of China[2018YFA0507000] ; Novo Nordisk-CAS Research Fund[NNCAS-2017-1-CC] ; National Health and Medical Research Council of Australia (NHMRC)[1184726] ; National Health and Medical Research Council of Australia (NHMRC)[1126857] ; National Health and Medical Research Council of Australia (NHMRC)[1150083] ; Takeda Science Foundation 2019 Medical Research Grant ; Japan Science and Technology Agency (JST)[PRESTO 18069571] |
| WOS研究方向 | Biochemistry & Molecular Biology |
| 语种 | 英语 |
| 出版者 | AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC |
| WOS记录号 | WOS:000552758600005 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/292157]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Wang, Ming-Wei; Wootten, Denise; Wu, Beili; Sexton, Patrick M. |
| 作者单位 | 1.Univ Tokyo, Grad Sch Med, Tokyo, Japan 2.Fudan Univ, Shanghai Med Coll, Sch Pharm, Shanghai, Peoples R China 3.Monash Univ, Monash Inst Pharmaceut Sci, Drug Discovery Biol, Parkville, Vic, Australia 4.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China 5.Univ Chinese Acad Sci, Beijing, Peoples R China 6.Natl Ctr Drug Screening, Shanghai, Peoples R China 7.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China |
| 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. |
入库方式： OAI收割
来源：上海药物研究所
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