5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology

doi:10.1016/j.cell.2018.01.001

	5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology
	Peng, Yao1,2,3 ; McCorvy, John D.4; Harpsoe, Kasper 5; Lansu, Katherine 4; Yuan, Shuguang 6; Popov, Petr 7,8,9; Qu, Lu 1,3; Pu, Mengchen1 ; Che, Tao 4; Nikolajsen, Louise F.1,5; Huang, Xi-Ping 4,10; Wu, Yiran1 ; Shen, Ling1,11 ; Bjorn-Yoshimoto, Walden E.5; Ding, Kang1,11 ; Wacker, Daniel 4; Han, Gye Won 7,8; Cheng, Jianjun1 ; Katritch, Vsevolod 7,8,9; Jensen, Anders A.5; Hanson, Michael A.12; Zhao, Suwen1,11 ; Gloriam, David E.5; Roth, Bryan L.4,10,13; Stevens, Raymond C.1,7,8,11 ; Liu, Zhi-Jie1,2,3,11
	2018-02-08
发表期刊	CELL (IF:45.5[JCR-2023],49.0[5-Year])
ISSN	0092-8674
卷号	172 期号:4 页码:719-+
发表状态	已发表
DOI	10.1016/j.cell.2018.01.001
摘要	Drugs frequently require interactions with multiple targets-via a process known as poly-pharmacology-to achieve their therapeutic actions. Currently, drugs targeting several serotonin receptors, including the 5-HT2C receptor, are useful for treating obesity, drug abuse, and schizophrenia. The competing challenges of developing selective 5-HT2C receptor ligands or creating drugs with a defined poly-pharmacological profile, especially aimed at G protein-coupled receptors (GPCRs), remain extremely difficult. Here, we solved two structures of the 5-HT2C receptor in complex with the highly promiscuous agonist ergotamine and the 5-HT2A-C receptor-selective inverse agonist ritanserin at resolutions of 3.0 angstrom and 2.7 angstrom, respectively. We analyzed their respective binding poses to provide mechanistic insights into their receptor recognition and opposing pharmacological actions. This study investigates the structural basis of polypharmacology at canonical GPCRs and illustrates how understanding characteristic patterns of ligand-receptor interaction and activation may ultimately facilitate drug design at multiple GPCRs.
收录类别	SCI ; SCIE
语种	英语
资助项目	Lundbeck Foundation[R163-2013-16327]
WOS研究方向	Biochemistry & Molecular Biology ; Cell Biology
WOS类目	Biochemistry & Molecular Biology ; Cell Biology
WOS记录号	WOS:000424648800013
出版者	CELL PRESS
WOS关键词	PROTEIN-COUPLED RECEPTORS ; SEROTONIN RECEPTOR ; MEMBRANE-PROTEINS ; CRYSTAL-STRUCTURE ; FUNCTIONAL SELECTIVITY ; DRUG DISCOVERY ; IN-VIVO ; AGONISTS ; LIGANDS ; SYSTEM
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/16246
专题	iHuman研究所_公共科研平台_同步辐射线站生命科学与技术学院 iHuman研究所 iHuman研究所_特聘教授组_Andrej Sali组 iHuman研究所_特聘教授组_Raymond Stevens组 iHuman研究所_PI研究组_刘志杰组 iHuman研究所_PI研究组_赵素文组 iHuman研究所_PI研究组_程建军组 iHuman研究所_科学装置(X)_膜蛋白同步辐射线站生命科学与技术学院_硕士生生命科学与技术学院_博士生
通讯作者	Roth, Bryan L.; Stevens, Raymond C.; Liu, Zhi-Jie
作者单位	1.ShanghaiTech Univ, iHuman Inst, Shanghai 201210, Peoples R China 2.Kunming Med Univ, Inst Mol & Clin Med, Yunnan Key Lab Stem Cell & Regenerat Med, Kunming 650500, Yunnan, Peoples R China 3.Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing 100101, Peoples R China 4.Univ North Carolina Chapel Hill, Dept Pharmacol, Chapel Hill, NC 27599 USA 5.Univ Copenhagen, Dept Drug Design & Pharmacol, Univ Pk 2, DK-2100 Copenhagen, Denmark 6.Ecole Polytech Fed Lausanne, Lab Phys Chem Polymers & Membranes, CH B3 495,Batiment CH,Stn 6, CH-1015 Lausanne, Switzerland 7.Univ Southern Calif, Michelson Ctr, Bridge Inst, Dept Biol Sci, Los Angeles, CA 90089 USA 8.Univ Southern Calif, Michelson Ctr, Bridge Inst, Dept Chem, Los Angeles, CA 90089 USA 9.Moscow Inst Phys & Technol, Dolgoprudnyi 141700, Russia 10.Univ North Carolina Chapel Hill, NIMH PDSP, Chapel Hill, NC 27599 USA 11.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 12.GPCR Consortium, San Marcos, CA 92078 USA 13.Univ North Carolina Chapel Hill, Eshelman Sch Pharm, Div Chem Biol & Med Chem, Chapel Hill, NC 27599 USA
第一作者单位	iHuman研究所
通讯作者单位	iHuman研究所; 生命科学与技术学院
第一作者的第一单位	iHuman研究所
推荐引用方式 GB/T 7714	Peng, Yao,McCorvy, John D.,Harpsoe, Kasper,et al. 5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology[J]. CELL,2018,172(4):719-+.
APA	Peng, Yao.,McCorvy, John D..,Harpsoe, Kasper.,Lansu, Katherine.,Yuan, Shuguang.,...&Liu, Zhi-Jie.(2018).5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology.CELL,172(4),719-+.
MLA	Peng, Yao,et al."5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology".CELL 172.4(2018):719-+.