Crystal structure of the human 5-HT1B serotonin receptor bound to an inverse agonist
文献类型：期刊论文
| 作者 | Yin, Wanchao1,2,3,4; Zhou, X. Edward1,4; Yang, Dehua3,5 ; de Waal, Parker W.4; Wang, Meitian6; Dai, Antao3,5; Cai, Xiaoqing3,5; Huang, Chia-Ying6; Liu, Ping1; Wang, Xiaoxi1
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| 刊名 | CELL DISCOVERY
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| 出版日期 | 2018-03-13 |
| 卷号 | 4 |
| ISSN号 | 2056-5968 |
| DOI | 10.1038/s41421-018-0009-2 |
| 文献子类 | Article |
| 英文摘要 | 5-hydroxytryptamine (5-HT, also known as serotonin) regulates many physiological processes through the 5-HT receptor family. Here we report the crystal structure of 5-HT1B subtype receptor (5-HT1BR) bound to the psychotropic serotonin receptor inverse agonist methiothepin (MT). Crystallization was facilitated by replacing ICL3 with a novel optimized variant of BRIL (OB1) that enhances the formation of intermolecular polar interactions, making OB1 a potential useful tool for structural studies of membrane proteins. Unlike the agonist ergotamine (ERG), MT occupies only the conserved orthosteric binding pocket, explaining the wide spectrum effect of MT on serotonin receptors. Compared with ERG, MT shifts toward TM6 and sterically pushes residues W327(6.48), F330(6.50) and F331(6.51) from inside the orthosteric binding pocket, leading to an outward movement of the extracellular end and a corresponding inward shift of the intracellular end of TM6, a feature shared by other reported inactive G protein-coupled receptor (GPCR) structures. Together with the previous agonist-bound serotonin receptor structures, the inverse agonist-bound 5-HT1BR structure identifies a basis for the ligand-mediated switch of 5-HT1BR activity and provides a structural understanding of the inactivation mechanism of 5-HT1BR and some other class A GPCRs, characterized by ligand-induced outward movement of the extracellular end of TM6 that is coupled with inward movement of the cytoplasmic end of this helix. |
| WOS关键词 | PROTEIN-COUPLED RECEPTOR ; 5-HYDROXYTRYPTAMINE(1B) RECEPTOR ; MOLECULAR-DYNAMICS ; SURFACE ENTROPY ; CRYSTALLIZATION ; RESOLUTION ; ACTIVATION ; GPCR ; MUTAGENESIS ; ANTAGONISTS |
| 资助项目 | National Natural Science Foundation[31300607] ; National Natural Science Foundation[81373463] ; Outstanding Young Scientist Foundation (CAS)[00000000] ; Youth Innovation Promotion Association of CAS[00000000] ; Van Andel Research Institute, Ministry of Science and Technology of China[2012ZX09301001] ; Van Andel Research Institute, Ministry of Science and Technology of China[2012CB910403] ; Van Andel Research Institute, Ministry of Science and Technology of China[2013CB910600] ; Van Andel Research Institute, Ministry of Science and Technology of China[XDB08020303] ; Van Andel Research Institute, Ministry of Science and Technology of China[2013ZX09507001] ; National Institutes of Health[DK071662] ; National Institutes of Health[GM102545] ; National Institutes of Health[GM104212] ; Shanghai Science and Technology Development Fund[15DZ2291600] ; Shanghai Science and Technology Development Fund[14431901200] ; CAS-Novo Nordisk Research Fund[00000000] |
| WOS研究方向 | Cell Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:000429190900001 |
| 出版者 | NATURE PUBLISHING GROUP |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279854]  |
| 专题 | 国家新药筛选中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 药物靶标结构与功能中心 |
| 通讯作者 | Wang, Ming-Wei; Xu, H. Eric; Jiang, Yi |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, VARI SIMM Ctr, Ctr Struct & Funct Drug Targets,CAS Key Lab Recep, Shanghai 201203, Peoples R China; 2.Univ Chinese Acad Sci, 19 A Yuquan Rd, Beijing 100049, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 4.Van Andel Res Inst, Lab Struct Sci, Grand Rapids, MI 49503 USA; 5.Natl Ctr Drug Screening, Shanghai 201203, Peoples R China; 6.Paul Scherrer Inst, Swiss Light Source, CH-5232 Villigen, Switzerland; 7.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 8.Trinity Coll Dublin, Sch Med, Membrane Struct & Funct Biol Grp, Dublin, Ireland; 9.Trinity Coll Dublin, Sch Biochem, Membrane Struct & Funct Biol Grp, Dublin, Ireland; 10.Trinity Coll Dublin, Sch Immunol, Membrane Struct & Funct Biol Grp, Dublin, Ireland; |
| 推荐引用方式 GB/T 7714 | Yin, Wanchao,Zhou, X. Edward,Yang, Dehua,et al. Crystal structure of the human 5-HT1B serotonin receptor bound to an inverse agonist[J]. CELL DISCOVERY,2018,4. |
| APA | Yin, Wanchao.,Zhou, X. Edward.,Yang, Dehua.,de Waal, Parker W..,Wang, Meitian.,...&Jiang, Yi.(2018).Crystal structure of the human 5-HT1B serotonin receptor bound to an inverse agonist.CELL DISCOVERY,4. |
| MLA | Yin, Wanchao,et al."Crystal structure of the human 5-HT1B serotonin receptor bound to an inverse agonist".CELL DISCOVERY 4(2018). |
入库方式： OAI收割
来源：上海药物研究所
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