Crystal structure of the human 5-HT1B serotonin receptor bound to an inverse agonist
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; Yin, Yanting1,4; Liu, Bo1; Zhou, Yu7; Wang, Jiang7; Liu, Hong7; Caffrey, Martin8,9,10; Melcher, Karsten4; Xu, Yechun3; Wang, Ming-Wei3,5,11,12; Xu, H. Eric1,4; Jiang, Yi1,4
2018-03-13
Source PublicationCELL DISCOVERY
ISSN2056-5968
Volume4
Status已发表
DOI10.1038/s41421-018-0009-2
Abstract5-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.
Indexed BySCI
Language英语
Funding ProjectShanghai Science and Technology Development Fund[15DZ2291600] ; Shanghai Science and Technology Development Fund[14431901200]
WOS Research AreaCell Biology
WOS SubjectCell Biology
WOS IDWOS:000429190900001
PublisherNATURE PUBLISHING GROUP
WOS KeywordPROTEIN-COUPLED RECEPTOR ; 5-HYDROXYTRYPTAMINE(1B) RECEPTOR ; MOLECULAR-DYNAMICS ; SURFACE ENTROPY ; CRYSTALLIZATION ; RESOLUTION ; ACTIVATION ; GPCR ; MUTAGENESIS ; ANTAGONISTS
Original Document TypeArticle
Citation statistics
Cited Times:29[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttps://kms.shanghaitech.edu.cn/handle/2MSLDSTB/20223
Collection生命科学与技术学院_特聘教授组_王明伟组
Corresponding AuthorWang, Ming-Wei; Xu, H. Eric; Jiang, Yi
Affiliation1.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
11.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China
12.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201203, Peoples R China
Corresponding Author AffilicationSchool of Life Science and Technology
Recommended Citation
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).
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