Structure of the glucagon receptor in complex with a glucagon analogue
文献类型：期刊论文
| 作者 | Zhang, Haonan2,3,4; Qiao, Anna2,3,4; Yang, Linlin5; Van Eps, Ned6; Frederiksen, Klaus S.7; Yang, Dehua2,8 ; Dai, Antao2,8; Cai, Xiaoqing2,8; Zhang, Hui2,4; Yi, Cuiying2
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| 刊名 | NATURE
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| 出版日期 | 2018-01-04 |
| 卷号 | 553期号:7686页码:106-+ |
| ISSN号 | 0028-0836 |
| DOI | 10.1038/nature25153 |
| 文献子类 | Article |
| 英文摘要 | Class B G-protein-coupled receptors (GPCRs), which consist of an extracellular domain (ECD) and a transmembrane domain (TMD), respond to secretin peptides to play a key part in hormonal homeostasis, and are important therapeutic targets for a variety of diseases(1-8). Previous work(9-11) has suggested that peptide ligands bind to class B GPCRs according to a two-domain binding model, in which the C-terminal region of the peptide targets the ECD and the N-terminal region of the peptide binds to the TMD binding pocket. Recently, three structures of class B GPCRs in complex with peptide ligands have been solved(12-14). These structures provide essential insights into peptide ligand recognition by class B GPCRs. However, owing to resolution limitations, the specific molecular interactions for peptide binding to class B GPCRs remain ambiguous. Moreover, these previously solved structures have different ECD conformations relative to the TMD, which introduces questions regarding inter-domain conformational flexibility and the changes required for receptor activation. Here we report the 3.0 angstrom-resolution crystal structure of the full-length human glucagon receptor (GCGR) in complex with a glucagon analogue and partial agonist, NNC1702. This structure provides molecular details of the interactions between GCGR and the peptide ligand. It reveals a marked change in the relative orientation between the ECD and TMD of GCGR compared to the previously solved structure of the inactive GCGR-NNC0640-mAb1 complex. Notably, the stalk region and the first extracellular loop undergo major conformational changes in secondary structure during peptide binding, forming key interactions with the peptide. We further propose a dual-binding-site trigger model for GCGR activation-which requires conformational changes of the stalk, first extracellular loop and TMD-that extends our understanding of the previously established two-domain peptide-binding model of class B GPCRs. |
| WOS关键词 | PROTEIN-COUPLED RECEPTOR ; CYCLASE-ACTIVATING POLYPEPTIDE ; CRYO-EM STRUCTURE ; CLASS-B GPCRS ; GLP-1 RECEPTOR ; PEPTIDE-1 RECEPTOR ; LIGAND-BINDING ; DOMAIN ; ANTAGONISTS ; REFINEMENT |
| 资助项目 | CAS Strategic Priority Research Program[XDB08020000] ; CAS[QYZDB-SSW-SMC024] ; CAS[QYZDB-SSW-SMC054] ; National Science Foundation of China[31422017] ; National Science Foundation of China[81525024] ; Shanghai Science and Technology Development Fund[15DZ2291600] ; E-Institutes of Shanghai Municipal Education Commission[E09013] ; Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund[U1501501] ; Canada Excellence Research Chairs program[00000000] ; Canadian Institute for Advanced Research[00000000] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| WOS记录号 | WOS:000419769300039 |
| 出版者 | NATURE PUBLISHING GROUP |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/272291]  |
| 专题 | 药物靶标结构与功能中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Zhao, Qiang; Wu, Beili |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 4.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China; 5.Zhengzhou Univ, Sch Basic Med Sci, Dept Pharmacol, 100 Sci Ave, Zhengzhou 450001, Henan, Peoples R China; 6.Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada; 7.Novo Nordisk AS, Novo Nordisk Pk, DK-2760 Malov, Denmark; 8.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, 189 Guo Shou Jing Rd, Shanghai 201203, Peoples R China; 9.Chinese Acad Sci, Inst Biophys, CAS Ctr Excellence Biomacromol, Natl Ctr Prot Sci,Natl Lab Biomacromol, Beijing 100101, Peoples R China; 10.East China Normal Univ, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, 500 Dongchuan Rd, Shanghai 200241, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Zhang, Haonan,Qiao, Anna,Yang, Linlin,et al. Structure of the glucagon receptor in complex with a glucagon analogue[J]. NATURE,2018,553(7686):106-+. |
| APA | Zhang, Haonan.,Qiao, Anna.,Yang, Linlin.,Van Eps, Ned.,Frederiksen, Klaus S..,...&Wu, Beili.(2018).Structure of the glucagon receptor in complex with a glucagon analogue.NATURE,553(7686),106-+. |
| MLA | Zhang, Haonan,et al."Structure of the glucagon receptor in complex with a glucagon analogue".NATURE 553.7686(2018):106-+. |
入库方式： OAI收割
来源：上海药物研究所
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