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Structural insights into the lipid and ligand regulation of serotonin receptors

文献类型：期刊论文

作者Xu, Peiyu1,2,3,4; Huang, Sijie3,4,5; Zhang, Huibing1,2,6,7,8; Mao, Chunyou1,2,6,7,8; Zhou, X. Edward9; Cheng, Xi10; Simon, Icaro A.11,12; Shen, Dan-Dan1,2,6,7,8; Yen, Hsin-Yung13; Robinson, Carol V.13
刊名NATURE
出版日期2021-03-24
页码25
ISSN号0028-0836
DOI10.1038/s41586-021-03376-8
通讯作者Jiang, Yi(yijiang@simm.ac.cn) ; Zhang, Yan(zhang_yan@zju.edu.cn) ; Xu, H. Eric(eric.xu@simm.ac.cn)
英文摘要Serotonin, or 5-hydroxytryptamine (5-HT), is an important neurotransmitter(1,2) that activates the largest subtype family of G-protein-coupled receptors(3). Drugs that target 5-HT1A, 5-HT1D, 5-HT1E and other 5-HT receptors are used to treat numerous disorders(4). 5-HT receptors have high levels of basal activity and are subject to regulation by lipids, but the structural basis for the lipid regulation and basal activation of these receptors and the pan-agonism of 5-HT remains unclear. Here we report five structures of 5-HT receptor-G-protein complexes: 5-HT1A in the apo state, bound to 5-HT or bound to the antipsychotic drug aripiprazole; 5-HT1D bound to 5-HT; and 5-HT1E in complex with a 5-HT1E- and 5-HT1F-selective agonist, BRL-54443. Notably, the phospholipid phosphatidylinositol 4-phosphate is present at the G-protein-5-HT1A interface, and is able to increase 5-HT1A-mediated G-protein activity. The receptor transmembrane domain is surrounded by cholesterol molecules-particularly in the case of 5-HT1A, in which cholesterol molecules are directly involved in shaping the ligand-binding pocket that determines the specificity for aripiprazol. Within the ligand-binding pocket of apo-5-HT1A are structured water molecules that mimic 5-HT to activate the receptor. Together, our results address a long-standing question of how lipids and water molecules regulate G-protein-coupled receptors, reveal how 5-HT acts as a pan-agonist, and identify the determinants of drug recognition in 5-HT receptors.
资助项目National Key R&D Programs of China[2018YFA0507002] ; Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; CAS Strategic Priority Research Program[XDB37030103] ; National Key Basic Research Program of China[2019YFA0508800] ; National Natural Science Foundation of China[81922071] ; Zhejiang Province Natural Science Fund for Excellent Young Scholars[LR19H310001] ; Fundamental Research Funds for the Central Universities[2019XZZX001-01-06] ; National Natural Science Foundation[31770796] ; National Science and Technology Major Project[2018ZX09711002-002-002] ; Fund of Youth Innovation Promotion Association[2018319 Y8G7011009] ; Jack Ma Foundation[2020-CMKYGG-05] ; EU[765657] ; Lundbeck Foundation[R163-2013-16327] ; Novo Nordisk Foundation[NNF18OC0031226] ; Wellcome Trust Investigator Award[104633/Z/14/Z] ; Science and Technology Commission of Shanghai Municipal[20431900100]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:000632421900001
出版者NATURE RESEARCH
源URL[http://119.78.100.183/handle/2S10ELR8/295562]  
专题新药研究国家重点实验室
通讯作者Jiang, Yi; Zhang, Yan; Xu, H. Eric
作者单位1.Zhejiang Univ, Sch Med, Sir Run Run Shaw Hosp, Dept Biophys, Hangzhou, Peoples R China
2.Zhejiang Univ, Sch Med, Sir Run Run Shaw Hosp, Dept Pathol, Hangzhou, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China
4.Univ Chinese Acad Sci, Beijing, Peoples R China
5.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
6.Zhejiang Univ, Liangzhu Lab, Med Ctr, Hangzhou, Peoples R China
7.Zhejiang Univ, MOE Frontier Sci Ctr Brain Res & Brain Machine In, Sch Med, Hangzhou, Peoples R China
8.Zheijang Prov Key Lab Immun & Inflammatory Dis, Hangzhou, Peoples R China
9.Van Andel Inst, Dept Struct Biol, Grand Rapids, MI USA
10.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Xu, Peiyu,Huang, Sijie,Zhang, Huibing,et al. Structural insights into the lipid and ligand regulation of serotonin receptors[J]. NATURE,2021:25.
APA Xu, Peiyu.,Huang, Sijie.,Zhang, Huibing.,Mao, Chunyou.,Zhou, X. Edward.,...&Xu, H. Eric.(2021).Structural insights into the lipid and ligand regulation of serotonin receptors.NATURE,25.
MLA Xu, Peiyu,et al."Structural insights into the lipid and ligand regulation of serotonin receptors".NATURE (2021):25.

入库方式： OAI收割

来源：上海药物研究所

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