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A unique hormonal recognition feature of the human glucagon-like peptide-2 receptor

文献类型：期刊论文

作者Sun, Wen11,12,13; Chen, Li-Nan9,10; Zhou, Qingtong7,8; Zhao, Li-Hua13; Yang, Dehua12,13; Zhang, Huibing9,10; Cong, Zhaotong6; Shen, Dan-Dan9,10; Zhao, Fenghui6; Zhou, Fulai12,13
刊名CELL RESEARCH
出版日期2020-11-25
页码11
ISSN号1001-0602
DOI10.1038/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.
WOS关键词CRYO-EM STRUCTURE ; PROTEIN-COUPLED RECEPTOR ; GLP-1 RECEPTOR ; STRUCTURAL BASIS ; IMMUNOHISTOCHEMICAL DETERMINATION ; CRYSTAL-STRUCTURE ; ACTIVATION ; COMPLEX ; BINDING ; DOMAIN
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研究方向Cell Biology
语种英语
出版者SPRINGERNATURE
WOS记录号WOS:000592609300001
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.Key Lab Immun & Inflammatory Dis Zhejiang Prov, Hangzhou 310058, Zhejiang, Peoples R China
3.Zhejiang Univ, Sch Med, MOE Frontier Sci Ctr Brain Res & Brain Machine In, Hangzhou 310058, Zhejiang, Peoples R China
4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
5.Univ Copenhagen, Dept Biomed Sci, DK-2200 Copenhagen N, Denmark
6.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China
7.Fudan Univ, Sch Basic Med Sci, Shanghai 200032, Peoples R China
8.ShanghaiTech Univ, IHuman Inst, Shanghai 201210, Peoples R China
9.Zhejiang Univ, Sch Med, Sir Run Run Shaw Hosp, Dept Pathol, Hangzhou 310058, Zhejiang, Peoples R China
10.Zhejiang Univ, Sch Med, Sir Run Run Shaw Hosp, Dept Biophys, Hangzhou 310058, Zhejiang, 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.

入库方式： OAI收割

来源：上海药物研究所

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