Crystal structure of the human 5-HT1B serotonin receptor bound to an inverse agonist

doi:10.1038/s41421-018-0009-2

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	Crystal structure of the human 5-HT1B serotonin receptor bound to an inverse agonist
	Yin, Wanchao 1,2,3,4; Zhou, X. Edward 1,4; Yang, Dehua3,5 ; de Waal, Parker W.4; Wang, Meitian 6; Dai, Antao 3,5; Cai, Xiaoqing 3,5; Huang, Chia-Ying 6; Liu, Ping 1; Wang, Xiaoxi 1
刊名	CELL DISCOVERY
	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.
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关键词	PROTEIN-COUPLED RECEPTOR ; 5-HYDROXYTRYPTAMINE(1B) RECEPTOR ; MOLECULAR-DYNAMICS ; SURFACE ENTROPY ; CRYSTALLIZATION ; RESOLUTION ; ACTIVATION ; GPCR ; MUTAGENESIS ; ANTAGONISTS
WOS研究方向	Cell Biology
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000429190900001
内容类型	期刊论文
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).