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

doi:10.1038/s41422-020-00442-0

	A unique hormonal recognition feature of the human glucagon-like peptide-2 receptor
	Sun, Wen 1,2,3; Chen, Li-Nan 4,5; Zhou, Qingtong6,7 ; Zhao, Li-Hua 1; Yang, Dehua 1,2; Zhang, Huibing 4,5; Cong, Zhaotong 8; Shen, Dan-Dan 4,5; Zhao, Fenghui 8; Zhou, Fulai 1,2; Cai, Xiaoqing 1,2; Chen, Yan 8; Zhou, Yan 1,2; Gadgaard, Sarina 9; van der Velden, Wijnand J. C.9; Zhao, Suwen6,10 ; Jiang, Yi 1; Rosenkilde, Mette M.9; Xu, H. Eric 1,3; Zhang, Yan 4,5,11,12,13; Wang, Ming-Wei1,2,3,7,8,10
	2020-12
发表期刊	CELL RESEARCH (IF:28.1[JCR-2023],36.4[5-Year])
ISSN	1001-0602
发表状态	已发表
DOI	10.1038/s41422-020-00442-0
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.
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收录类别	SCI ; SCIE
语种	英语
资助项目	National Natural Science Foundation of China[81872915][81922071][81773792][81973373][21704064][31770796][31971178] ; National Science & Technology Major Project of China - Key New Drug Creation and Manufacturing Program[2018ZX09735-001][2018ZX09711002-002-005][2018ZX09711002-002-002] ; National Key Basic Research Program of China[2018YFA0507000][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] ; 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
WOS类目	Cell Biology
WOS记录号	WOS:000592609300001
出版者	SPRINGERNATURE
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/124604
专题	iHuman研究所_PI研究组_赵素文组 iHuman研究所_特聘教授组_Andrej Sali组生命科学与技术学院_特聘教授组_王明伟组
通讯作者	Xu, H. Eric; Zhang, Yan; Wang, Ming-Wei
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 4.Zhejiang Univ, Sch Med, Sir Run Run Shaw Hosp, Dept Biophys, Hangzhou 310058, Zhejiang, Peoples R China 5.Zhejiang Univ, Sch Med, Sir Run Run Shaw Hosp, Dept Pathol, Hangzhou 310058, Zhejiang, Peoples R China 6.ShanghaiTech Univ, IHuman Inst, Shanghai 201210, Peoples R China 7.Fudan Univ, Sch Basic Med Sci, Shanghai 200032, Peoples R China 8.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China 9.Univ Copenhagen, Dept Biomed Sci, DK-2200 Copenhagen N, Denmark 10.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 11.Zhejiang Univ, Sch Med, MOE Frontier Sci Ctr Brain Res & Brain Machine In, Hangzhou 310058, Zhejiang, Peoples R China 12.Key Lab Immun & Inflammatory Dis Zhejiang Prov, Hangzhou 310058, Zhejiang, Peoples R China 13.Zhejiang Univ, Med Ctr, Zhejiang Lab Syst & Precis Med, Hangzhou 311121, Zhejiang, Peoples R China
通讯作者单位	生命科学与技术学院
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.
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.
MLA	Sun, Wen,et al."A unique hormonal recognition feature of the human glucagon-like peptide-2 receptor".CELL RESEARCH (2020).