中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
  4. 药物靶标结构与功能中心
An intrinsic agonist mechanism for activation of glucagon-like peptide-1 receptor by its extracellular domain

文献类型：期刊论文

作者Yin, Yanting1,2,3,4; Zhou, X. Edward3,4; Hou, Li2; Zhao, Li-Hua2; Liu, Bo2; Wang, Gaihong2; Jiang, Yi2; Melcher, Karsten3,4; Xu, H. Eric1,2,3,4
刊名CELL DISCOVERY
出版日期2016-11-22
卷号2
关键词GLP-1R class B GPCR intrinsic agonist glucagon-like peptide-1 exendin-4 BETP
ISSN号2056-5968
DOI10.1038/celldisc.2016.42
文献子类Article
英文摘要The glucagon-like peptide-1 receptor is a class B G protein coupled receptor (GPCR) that plays key roles in glucose metabolism and is a major therapeutic target for diabetes. The classic two-domain model for class B GPCR activation proposes that the apo-state receptor is auto-inhibited by its extracellular domain, which physically interacts with the transmembrane domain. The binding of the C-terminus of the peptide hormone to the extracellular domain allows the N-terminus of the hormone to insert into the transmembrane domain to induce receptor activation. In contrast to this model, here we demonstrate that glucagon-like peptide-1 receptor can be activated by N-terminally truncated glucagon-like peptide-1 or exendin-4 when fused to the receptor, raising the question regarding the role of N-terminal residues of peptide hormone in glucagon-like peptide-1 receptor activation. Mutations of cysteine 347 to lysine or arginine in intracellular loop 3 transform the receptor into a G protein-biased receptor and allow it to be activated by a nonspecific five-residue linker that is completely devoid of exendin-4 or glucagon-like peptide-1 sequence but still requires the presence of an intact extracellular domain. Moreover, the extracellular domain can activate the receptor in trans in the presence of an intact peptide hormone, and specific mutations in three extracellular loops abolished this extracellular domain trans-activation. Together, our data reveal a dominant role of the extracellular domain in glucagon-like peptide-1 receptor activation and support an intrinsic agonist model of the extracellular domain, in which peptide binding switches the receptor from the auto-inhibited state to the auto-activated state by releasing the intrinsic agonist activity of the extracellular domain.
WOS关键词PROTEIN-COUPLED-RECEPTOR ; CLASS-B GPCR ; CORTICOTROPIN-RELEASING-FACTOR ; CRYSTAL-STRUCTURE ; INSULIN-SECRETION ; GLP-1 RECEPTOR ; MOLECULAR RECOGNITION ; STRUCTURAL BASIS ; BINDING POCKET ; CGRP RECEPTOR
资助项目National Natural Science Foundation of China[31300245] ; National Natural Science Foundation of China[31300607] ; Jay and Betty Van Andel Foundation[00000000] ; Ministry of Science and Technology of China[2012ZX09301001] ; Ministry of Science and Technology of China[2012CB910403] ; Ministry of Science and Technology of China[2013CB910600] ; Ministry of Science and Technology of China[XDB08020303] ; Amway (China)[00000000] ; National Institutes of Health[DK071662] ; National Institutes of Health[GM102545] ; National Institutes of Health[GM104212] ; Shanghai Science and Technology Committee[13ZR1447600] ; Shanghai Rising-Star Program[14QA1404300]
WOS研究方向Cell Biology
语种英语
WOS记录号WOS:000414898800001
出版者NATURE PUBLISHING GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/275801]  
专题药物靶标结构与功能中心
通讯作者Melcher, Karsten; Xu, H. Eric
作者单位1.Univ Chinese Acad Sci, Beijing, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Struct & Funct Drug Targets, Key Lab Receptor Res,VARI SIMM Ctr, Shanghai, Peoples R China;
3.Van Andel Res Inst, Lab Struct Sci, Grand Rapids, MI 49503 USA;
4.Van Andel Res Inst, Lab Struct Biol & Biochem, Grand Rapids, MI 49503 USA;
推荐引用方式
GB/T 7714		 Yin, Yanting,Zhou, X. Edward,Hou, Li,et al. An intrinsic agonist mechanism for activation of glucagon-like peptide-1 receptor by its extracellular domain[J]. CELL DISCOVERY,2016,2.
APA Yin, Yanting.,Zhou, X. Edward.,Hou, Li.,Zhao, Li-Hua.,Liu, Bo.,...&Xu, H. Eric.(2016).An intrinsic agonist mechanism for activation of glucagon-like peptide-1 receptor by its extracellular domain.CELL DISCOVERY,2.
MLA Yin, Yanting,et al."An intrinsic agonist mechanism for activation of glucagon-like peptide-1 receptor by its extracellular domain".CELL DISCOVERY 2(2016).

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

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。