Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators
文献类型：期刊论文
| 作者 | Song, Gaojie12; Yang, Dehua10,11 ; Wang, Yuxia12; de Graaf, Chris9; Zhou, Qingtong12; Jiang, Shanshan8; Liu, Kaiwen6,7,12; Cai, Xiaoqing10,11; Dai, Antao10,11; Lin, Guangyao7
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| 刊名 | NATURE
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| 出版日期 | 2017-06-08 |
| 卷号 | 546期号:7657页码:312-+ |
| ISSN号 | 0028-0836 |
| DOI | 10.1038/nature22378 |
| 文献子类 | Article |
| 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. |
| WOS关键词 | GLUCAGON-LIKE PEPTIDE-1 ; PROTEIN-COUPLED RECEPTORS ; MOLECULAR SIMULATION ; CRYSTAL-STRUCTURE ; FORCE-FIELD ; LIGAND ; ANTAGONIST ; AGONIST ; BINDING ; DETERMINANTS |
| 资助项目 | National Natural Science Foundation of China[31330019] ; National Natural Science Foundation of China[31500593] ; National Natural Science Foundation of China[81373463] ; National Natural Science Foundation of China[81573479] ; National Health and Family Planning Commission[2012ZX09304-011] ; National Health and Family Planning Commission[2013ZX09401003-005] ; National Health and Family Planning Commission[2013ZX09507001] ; National Health and Family Planning Commission[2013ZX09507-002] ; Shanghai Science and Technology Development Fund[15DZ2291600] ; Ministry of Science and Technology of China[2014CB910400] ; Ministry of Science and Technology of China[2015CB910104] ; Netherlands eScience Center (NLeSC)/NWO Enabling Technologies project: 3D-e-Chem[027.014.201] ; European Cooperation in Science and Technology Action GLISTEN[CM1207] ; National Key Research and Development Program of China[2016YCF0905902] ; Cloning, Cell Expression and Protein Purification Core Facilities of iHuman Institute[00000000] ; Shanghai Municipal Government[00000000] ; ShanghaiTech University[00000000] ; GPCR Consortium[00000000] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| 出版者 | NATURE PUBLISHING GROUP |
| WOS记录号 | WOS:000402823400042 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/272614]  |
| 专题 | 国家新药筛选中心 |
| 通讯作者 | Liu, Zhi-Jie; Wang, Ming-Wei; Stevens, Raymond C. |
| 作者单位 | 1.Kunming Med Univ, Inst Mol & Clin Med, Kunming 650500, Peoples R China 2.GPCR Consortium, San Marcos, CA 92078 USA; 3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 4.Novo Nordisk, DK-2760 Malov, Denmark; 5.Univ Southern Calif, Bridge Inst, Dept Chem, 3430 S Vermont Ave, Los Angeles, CA 90089 USA; 6.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China; 7.ShanghaiTech Univ, Sch Life Sci & Technol, 393 Middle Huaxia Rd, Shanghai 201210, Peoples R China; 8.Fudan Univ, Sch Pharm, 826 Zhang Heng Rd, Shanghai 201203, Peoples R China; 9.Vrije Univ Amsterdam, Fac Sci, Div Med Chem, AIMMS, De Boelelaan 1108, NL-1081 HZ Amsterdam, Netherlands; 10.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 189 Guo Shou Jing Rd, Shanghai 201203, 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-+. |
入库方式： OAI收割
来源：上海药物研究所
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