Structural insights into the human D1 and D2 dopamine receptor signaling complexes

doi:10.1016/j.cell.2021.01.027

	Structural insights into the human D1 and D2 dopamine receptor signaling complexes
	Zhuang, Youwen 4,5; Xu, Peiyu 4,5,6,7; Mao, Chunyou 6,7,8,9; Wang, Lei 10; Krumm, Brian 11; Zhou, X. Edward 1; Huang, Sijie 4,5,12; Liu, Heng 10; Cheng, Xi 2,4; Huang, Xi-Ping 11
刊名	CELL
	2021-02-18
卷号	184 期号:4 页码:931-+
ISSN号	0092-8674
DOI	10.1016/j.cell.2021.01.027
通讯作者	Roth, Bryan L.(bryan_roth@med.unc.edu) ; Zhang, Yan(zhang_yan@zju.edu.cn) ; Zhang, Cheng(chengzh@pitt.edu) ; Xu, H. Eric(eric.xu@simm.ac.cn)
英文摘要	The D1- and D2-dopamine receptors (D1R and D2R), which signal through G(s) and G(i), respectively, represent the principal stimulatory and inhibitory dopamine receptors in the central nervous system. D1R and D2R also represent the main therapeutic targets for Parkinson's disease, schizophrenia, and many other neuropsychiatric disorders, and insight into their signaling is essential for understanding both therapeutic and side effects of dopaminergic drugs. Here, we report four cryoelectron microscopy (cryo-EM) structures of D1R-G(s) and D2R-G(i) signaling complexes with selective and non-selective dopamine agonists, including two currently used anti-Parkinson's disease drugs, apomorphine and bromocriptine. These structures, together with mutagenesis studies, reveal the conserved binding mode of dopamine agonists, the unique pocket topology underlying ligand selectivity, the conformational changes in receptor activation, and potential structural determinants for G protein-coupling selectivity. These results provide both a molecular understanding of dopamine signaling and multiple structural templates for drug design targeting the dopaminergic system.
资助项目	National Key R&D Programs of China[2018YFA0507002] ; National Key R&D Programs of China[2019YFA0508800] ; Shanghai Municipal Science and Technology Major Projects[2019SHZDZX02] ; CAS Strategic Priority Research Program[XDB37030103] ; National Natural Science Foundation of China[81922071] ; National Natural Science Foundation of China[31770796] ; Zhejiang Province Natural Science Fund for Excellent Young Scholars[LR19H310001] ; Fundamental Research Funds for the Central Universities[2019XZZX001-01-06] ; Science and Technology Commission of Shanghai Municipality[20431900100] ; Jack Ma Foundation[2020-CMKYGG-05] ; National Science and Technology Major Projects[2018ZX09711002-002-002] ; NIMH (Psychoactive Drug Screening Program)[RO1MH112205] ; NIH[R35GM128641]
WOS研究方向	Biochemistry & Molecular Biology ; Cell Biology
语种	英语
出版者	CELL PRESS
WOS记录号	WOS:000629633400010
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/295411]
专题	中国科学院上海药物研究所
通讯作者	Roth, Bryan L.; Zhang, Yan; Zhang, Cheng; Xu, H. Eric
作者单位	1.Van Andel Res Inst, Ctr Canc & Cell Biol, Program Struct Biol, Grand Rapids, MI USA 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Zhejiang Prov Key Lab Immun & Inflammatory Dis, Hangzhou 310058, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China 5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 6.Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Biophys, Sch Med, Hangzhou 310058, Peoples R China 7.Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Pathol, Sch Med, Hangzhou 310058, Peoples R China 8.Zhejiang Univ, Zhejiang Lab Syst & Precison Med, Med Ctr, Hangzhou 311121, Peoples R China 9.Zhejiang Univ, MOE Frontier Sci Ctr Brain Res & Brain Machine In, Sch Med, Hangzhou 310058, Peoples R China 10.Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA 15213 USA
推荐引用方式 GB/T 7714	Zhuang, Youwen,Xu, Peiyu,Mao, Chunyou,et al. Structural insights into the human D1 and D2 dopamine receptor signaling complexes[J]. CELL,2021,184(4):931-+.
APA	Zhuang, Youwen.,Xu, Peiyu.,Mao, Chunyou.,Wang, Lei.,Krumm, Brian.,...&Xu, H. Eric.(2021).Structural insights into the human D1 and D2 dopamine receptor signaling complexes.CELL,184(4),931-+.
MLA	Zhuang, Youwen,et al."Structural insights into the human D1 and D2 dopamine receptor signaling complexes".CELL 184.4(2021):931-+.