Structural genomics of the human dopamine receptor system  

作　　者：Peiyu Xu Sijie Huang Brian E.Krumm Youwen Zhuang Chunyou Mao Yumu Zhang Yue Wang Xi-Ping Huang Yong-Feng Liu Xinheng He Huadong Li Wanchao Yin Yi Jiang Yan Zhang Bryan L.Roth H.Eric Xu 

机构地区：[1]State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,China [2]Department of Pharmacology,University of North Carolina Chapel Hill Medical School,Chapel Hill,NC,USA [3]Center for Structural Pharmacology and Therapeutics Development,Sir Run Run Shaw Hospital,Zhejiang University School of Medicine,Hangzhou,Zhejiang,China [4]Department of General Surgery,Sir Run Run Shaw Hospital,Zhejiang University School of Medicine,Hangzhou,Zhejiang,China [5]University of Chinese Academy of Sciences,Beijing,China [6]School of Life Science and Technology,ShanghaiTech University,Shanghai,China [7]Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital,Zhejiang University School of Medicine,Hangzhou,Zhejiang,China [8]MOE Frontier Science Center for Brain Research and Brain-Machine Integration,Zhejiang University School of Medicine,Hangzhou,Zhejiang,China [9]Liangzhu Laboratory,Zhejiang University Medical Center,Hangzhou,Zhejiang,China [10]McGovern Institute for Brain Research,Massachusetts Institute of Technology,Cambridge,MA,USA [11]Department of Pharmaceutical Chemistry,University of California San Francisco,San Francisco,CA,USA

出　　处：《Cell Research》2023年第8期604-616,共13页细胞研究（英文版）

基　　金：the National Key R&D Programs of China(2018YFA0507002)’Shanghai Municipal Science and Technology Major Project(2019SHZDZX02 and XDB08020303)to H.E.X.;the National Key Basic Research Program of China(2019YFA0508800)‘the Key R&D Projects of Zhejiang Province(2021C03039);Fundamental Research Funds for the Central Universities(2019XZZX001-01-06)to Yan Z.;the Zhejiang Province Natural Science Fund for Excellent Young Scholars(LR22C050002);the National Natural Science Foundation of China(32100959)to C.M.;the National Natural Science Foundation of China(31770796);the National Science and Technology Major Project(2018ZX09711002)to Y.J.;grants from the NIMH Psychoactive Drug Screening Program to X.-P.H.,Y.L.,B.L.R.,and RO1MH112205 to B.E.K.and B.L.R.The Special Research Assistant Project of Chinese Academy of Sciences to Youwen Z.

摘　　要：The dopaminergic system,including five dopamine receptors(D1R to D5R),plays essential roles in the central nervous system(CNS);and ligands that activate dopamine receptors have been used to treat many neuropsychiatric disorders,including Parkinson’s Disease(PD)and schizophrenia.Here,we report cryo-EM structures of all five subtypes of human dopamine receptors in complex with G protein and bound to the pan-agonist,rotigotine,which is used to treat PD and restless legs syndrome.The structures reveal the basis of rotigotine recognition in different dopamine receptors.Structural analysis together with functional assays illuminate determinants of ligand polypharmacology and selectivity.The structures also uncover the mechanisms of dopamine receptor activation,unique structural features among the five receptor subtypes,and the basis of G protein coupling specificity.Our work provides a comprehensive set of structural templates for the rational design of specific ligands to treat CNS diseases targeting the dopaminergic system.

关 键 词：DOPAMINE SPECIFICITY SYSTEM 

分 类 号：R97[医药卫生—药品]