A unique hormonal recognition feature of the human glucagon-like peptide-2 receptor | |
Sun, Wen5,6,7; Chen, Li-Nan8,9; Zhou, Qingtong10,11; Zhao, Li-Hua5; Yang, Dehua5,6; Zhang, Huibing8,9; Cong, Zhaotong12; Shen, Dan-Dan8,9; Zhao, Fenghui12; Zhou, Fulai5,6 | |
刊名 | CELL RESEARCH |
2020-11-25 | |
页码 | 11 |
ISSN号 | 1001-0602 |
DOI | 10.1038/s41422-020-00442-0 |
通讯作者 | Xu, H. Eric(eric.xu@simm.ac.cn) ; Zhang, Yan(zhang_yan@zju.edu.cn) ; Wang, Ming-Wei(mwwang@simm.ac.cn) |
英文摘要 | Glucagon-like peptides (GLP-1 and GLP-2) are two proglucagon-derived intestinal hormones that mediate distinct physiological functions through two related receptors (GLP-1R and GLP-2R) which are important drug targets for metabolic disorders and Crohn's disease, respectively. Despite great progress in GLP-1R structure determination, our understanding on the differences of peptide binding and signal transduction between these two receptors remains elusive. Here we report the electron microscopy structure of the human GLP-2R in complex with GLP-2 and a G(s) heterotrimer. To accommodate GLP-2 rather than GLP-1, GLP-2R fine-tunes the conformations of the extracellular parts of transmembrane helices (TMs) 1, 5, 7 and extracellular loop 1 (ECL1). In contrast to GLP-1, the N-terminal histidine of GLP-2 penetrates into the receptor core with a unique orientation. The middle region of GLP-2 engages with TM1 and TM7 more extensively than with ECL2, and the GLP-2 C-terminus closely attaches to ECL1, which is the most protruded among 9 class B G protein-coupled receptors (GPCRs). Functional studies revealed that the above three segments of GLP-2 are essential for GLP-2 recognition and receptor activation, especially the middle region. These results provide new insights into the molecular basis of ligand specificity in class B GPCRs and may facilitate the development of more specific therapeutics. |
资助项目 | National Natural Science Foundation of China[81872915] ; National Natural Science Foundation of China[81922071] ; National Natural Science Foundation of China[81773792] ; National Natural Science Foundation of China[81973373] ; National Natural Science Foundation of China[21704064] ; National Natural Science Foundation of China[31770796] ; National Natural Science Foundation of China[31971178] ; National Science & Technology Major Project of China - Key New Drug Creation and Manufacturing Program[2018ZX09735-001] ; National Science & Technology Major Project of China - Key New Drug Creation and Manufacturing Program[2018ZX09711002-002-005] ; National Science & Technology Major Project of China - Key New Drug Creation and Manufacturing Program[2018ZX09711002-002-002] ; National Key Basic Research Program of China[2018YFA0507000] ; National Key Basic Research Program of China[2019YFA0508800] ; Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; Ministry of Science and Technology of China Major Project[XDB08020303] ; Zhejiang Province Science Fund for Distinguished Young Scholars[LR19H310001] ; Fundamental Research Funds for Central Universities[2019XZZX001-01-06] ; Shanghai Science and Technology Development Fund[18ZR1447800] ; Young Innovator Association of CAS[2018325] ; SA-SIBS Scholarship Program ; Fudan-SIMM Joint Research Fund[FU-SIMM-20174003] ; Novo Nordisk-CAS Research Fund grant[NNCAS-2017-1-CC] |
WOS关键词 | CRYO-EM STRUCTURE ; PROTEIN-COUPLED RECEPTOR ; GLP-1 RECEPTOR ; STRUCTURAL BASIS ; IMMUNOHISTOCHEMICAL DETERMINATION ; CRYSTAL-STRUCTURE ; ACTIVATION ; COMPLEX ; BINDING ; DOMAIN |
WOS研究方向 | Cell Biology |
语种 | 英语 |
出版者 | SPRINGERNATURE |
WOS记录号 | WOS:000592609300001 |
内容类型 | 期刊论文 |
源URL | [http://119.78.100.183/handle/2S10ELR8/292648] |
专题 | 中国科学院上海药物研究所 |
通讯作者 | Xu, H. Eric; Zhang, Yan; Wang, Ming-Wei |
作者单位 | 1.Zhejiang Univ, Med Ctr, Zhejiang Lab Syst & Precis Med, Hangzhou 311121, Zhejiang, Peoples R China 2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 3.Zhejiang Univ, Sch Med, MOE Frontier Sci Ctr Brain Res & Brain Machine In, Hangzhou 310058, Zhejiang, Peoples R China 4.Key Lab Immun & Inflammatory Dis Zhejiang Prov, Hangzhou 310058, Zhejiang, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China 7.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 8.Zhejiang Univ, Sch Med, Sir Run Run Shaw Hosp, Dept Biophys, Hangzhou 310058, Zhejiang, Peoples R China 9.Zhejiang Univ, Sch Med, Sir Run Run Shaw Hosp, Dept Pathol, Hangzhou 310058, Zhejiang, Peoples R China 10.ShanghaiTech Univ, IHuman Inst, Shanghai 201210, Peoples R China |
推荐引用方式 GB/T 7714 | Sun, Wen,Chen, Li-Nan,Zhou, Qingtong,et al. A unique hormonal recognition feature of the human glucagon-like peptide-2 receptor[J]. CELL RESEARCH,2020:11. |
APA | Sun, Wen.,Chen, Li-Nan.,Zhou, Qingtong.,Zhao, Li-Hua.,Yang, Dehua.,...&Wang, Ming-Wei.(2020).A unique hormonal recognition feature of the human glucagon-like peptide-2 receptor.CELL RESEARCH,11. |
MLA | Sun, Wen,et al."A unique hormonal recognition feature of the human glucagon-like peptide-2 receptor".CELL RESEARCH (2020):11. |
个性服务 |
查看访问统计 |
相关权益政策 |
暂无数据 |
收藏/分享 |
除非特别说明,本系统中所有内容都受版权保护,并保留所有权利。
修改评论