Cryo-electron microscopy structure of the glucagon receptor with a dual-agonist peptide

doi:10.1074/jbc.RA120.013793

	Cryo-electron microscopy structure of the glucagon receptor with a dual-agonist peptide
	Chang, Rulue 7; Zhang, Xin 1; Qiao, Anna 2,3; Dai, Antao 2,5; Belousoff, Matthew J.1; Tan, Qiuxiang 2,3; Shao, Lijun 2,3,6; Zhong, Li 2,3; Lin, Guangyao 2,3,6; Liang, Yi-Lynn 1
刊名	JOURNAL OF BIOLOGICAL CHEMISTRY
	2020-07-10
卷号	295 期号:28 页码:9313-9325
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
ISSN号	0021-9258
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.
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关键词	CRYO-EM STRUCTURE ; BEAM-INDUCED MOTION ; GLP-1 RECEPTOR ; BIASED AGONISM ; RECOGNITION ; RESIDUES ; DYNAMICS ; OBESITY
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
内容类型	期刊论文
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.Monash Univ, Monash Inst Pharmaceut Sci, Drug Discovery Biol, Parkville, Vic, Australia 2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China 3.Univ Chinese Acad Sci, Beijing, Peoples R China 4.Univ Tokyo, Grad Sch Med, Tokyo, Japan 5.Natl Ctr Drug Screening, Shanghai, Peoples R China 6.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 7.Fudan Univ, Shanghai Med Coll, Sch Pharm, 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.