Ligand recognition and biased agonism of the D1 dopamine receptor

被引:21
|
作者
Teng, Xiao [1 ,2 ]
Chen, Sijia [2 ,3 ]
Nie, Yingying [2 ]
Xiao, Peng [4 ,5 ]
Yu, Xiao [4 ,6 ]
Shao, Zhenhua [7 ,8 ]
Zheng, Sanduo [1 ,2 ,3 ]
机构
[1] Tsinghua Univ, Tsinghua Inst Multidisciplinary Biomed Res, Beijing, Peoples R China
[2] Natl Inst Biol Sci, Beijing, Peoples R China
[3] Peking Union Med Coll, Grad Sch, Beijing, Peoples R China
[4] Shandong Univ, Cheeloo Coll Med, Key Lab Expt Teratol, Minist Educ,Sch Basic Med Sci, Jinan, Shandong, Peoples R China
[5] Shandong Univ, Cheeloo Coll Med, Sch Basic Med Sci, Dept Biochem & Mol Biol, Jinan, Shandong, Peoples R China
[6] Shandong Univ, Cheeloo Coll Med, Sch Basic Med Sci, Dept Physiol, Jinan, Shandong, Peoples R China
[7] Sichuan Univ, West China Hosp, Div Nephrol, Chengdu, Sichuan, Peoples R China
[8] Sichuan Univ, West China Hosp, Kidney Res Inst, State Key Lab Biotherapy & Canc Ctr, Chengdu, Sichuan, Peoples R China
关键词
DYNAMICS; VALIDATION; BETA(2)AR; MECHANISM; INSIGHTS; MODEL;
D O I
10.1038/s41467-022-30929-w
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Dopamine receptors are widely distributed in the central nervous system and are important therapeutic targets for treatment of various psychiatric and neurological diseases. Here, we report three cryo-electron microscopy structures of the D1 dopamine receptor (D1R)-Gs complex bound to two agonists, fenoldopam and tavapadon, and a positive allosteric modulator LY3154207. The structure reveals unusual binding of two fenoldopam molecules, one to the orthosteric binding pocket (OBP) and the other to the extended binding pocket (EBP). In contrast, one elongated tavapadon molecule binds to D1R, extending from OBP to EBP. Moreover, LY3154207 stabilizes the second intracellular loop of D1R in an alpha helical conformation to efficiently engage the G protein. Through a combination of biochemical, biophysical and cellular assays, we further show that the broad conformation stabilized by two fenoldopam molecules and interaction between TM5 and the agonist are important for biased signaling of D1R. D1 dopamine receptor is an important drug target for treatment of hypertension and Parkinson's disease. Here, authors report three cryo-EM structures of the D1R-Gs complex bound to three distinct D1R-selective drugs.
引用
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页数:11
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