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DOI | 10.1016/j.enpol.2016.10.044 |
Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators | |
Song, Gaojie1; Yang, Dehua2,3; Wang, Yuxia1; de Graaf, Chris4; Zhou, Qingtong1; Jiang, Shanshan5; Liu, Kaiwen1,6,7; Cai, Xiaoqing2,3; Dai, Antao2,3; Lin, Guangyao6; Liu, Dongsheng1; Wu, Fan1,6,7; Wu, Yiran1; Zhao, Suwen1,6; Ye, Li5; Han, Gye Won8; Lau, Jesper9; Wu, Beili6,7,10; Hanson, Michael A.11; Liu, Zhi-Jie1,6,12; Wang, Ming-Wei2,3,5,6; Stevens, Raymond C.1,6 | |
2017-06-08 | |
发表期刊 | NATURE |
ISSN | 0028-0836 |
EISSN | 1476-4687 |
出版年 | 2017 |
卷号 | 546期号:7657页码:312-+ |
文章类型 | Article |
语种 | 英语 |
国家 | Peoples R China; Netherlands; USA; Denmark |
英文摘要 | The glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR) are members of the secretin-like class B family of G-protein-coupled receptors (GPCRs) and have opposing physiological roles in insulin release and glucose homeostasis(1). The treatment of type 2 diabetes requires positive modulation of GLP-1R to inhibit glucagon secretion and stimulate insulin secretion in a glucose-dependent manner(2). Here we report crystal structures of the human GLP-1R transmembrane domain in complex with two different negative allosteric modulators, PF-06372222 and NNC0640, at 2.7 and 3.0 angstrom resolution, respectively. The structures reveal a common binding pocket for negative allosteric modulators, present in both GLP-1R and GCGR(3) and located outside helices V-VII near the intracellular half of the receptor. The receptor is in an inactive conformation with compounds that restrict movement of the intracellular tip of helix VI, a movement that is generally associated with activation mechanisms in class A GPCRs(4-6). Molecular modelling and mutagenesis studies indicate that agonist positive allosteric modulators target the same general region, but in a distinct sub-pocket at the interface between helices V and VI, which may facilitate the formation of an intracellular binding site that enhances G-protein coupling. |
领域 | 地球科学 ; 气候变化 ; 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000402823400042 |
WOS关键词 | GLUCAGON-LIKE PEPTIDE-1 ; CRYSTAL-STRUCTURE ; FORCE-FIELD ; PROTEIN ; LIGAND ; AGONIST ; BINDING ; DETERMINANTS ; VALIDATION ; ANTAGONIST |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/18573 |
专题 | 气候变化 |
作者单位 | 1.ShanghaiTech Univ, iHuman Inst, 393 Middle Huaxia Rd, Shanghai 201210, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, 189 Guo Shou Jing Rd, Shanghai 201203, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 189 Guo Shou Jing Rd, Shanghai 201203, Peoples R China; 4.Vrije Univ Amsterdam, Fac Sci, Div Med Chem, AIMMS, De Boelelaan 1108, NL-1081 HZ Amsterdam, Netherlands; 5.Fudan Univ, Sch Pharm, 826 Zhang Heng Rd, Shanghai 201203, Peoples R China; 6.ShanghaiTech Univ, Sch Life Sci & Technol, 393 Middle Huaxia Rd, Shanghai 201210, Peoples R China; 7.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China; 8.Univ Southern Calif, Bridge Inst, Dept Chem, 3430 S Vermont Ave, Los Angeles, CA 90089 USA; 9.Novo Nordisk, DK-2760 Malov, Denmark; 10.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 11.GPCR Consortium, San Marcos, CA 92078 USA; 12.Kunming Med Univ, Inst Mol & Clin Med, Kunming 650500, Peoples R China |
推荐引用方式 GB/T 7714 | Song, Gaojie,Yang, Dehua,Wang, Yuxia,et al. Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators[J]. NATURE,2017,546(7657):312-+. |
APA | Song, Gaojie.,Yang, Dehua.,Wang, Yuxia.,de Graaf, Chris.,Zhou, Qingtong.,...&Stevens, Raymond C..(2017).Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators.NATURE,546(7657),312-+. |
MLA | Song, Gaojie,et al."Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators".NATURE 546.7657(2017):312-+. |
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