Volume 31, No 5, May 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 5, May 2021: 593-596   |  Open Access

LETTERS TO THE EDITOR

Mechanism of dopamine binding and allosteric modulation of the human D1 dopamine receptor

Youwen Zhuang^1,2 , Brian Krumm³ , Huibing Zhang^4,5 , X. Edward Zhou⁶ , Yue Wang^1,2 , Xi-Ping Huang³ , Yongfeng Liu³ , Xi Cheng⁷ , Yi Jiang^1,2 , Hualiang Jiang⁷ , Cheng Zhang⁸ , Wei Yi⁹ , Bryan L. Roth^3,* , Yan Zhang^4,5,10,* , H. Eric Xu^1,2,*

¹The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
²University of Chinese Academy of Sciences, Beijing 100049, China
³Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA
⁴Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
⁵MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
⁶Center for Cancer and Cell Biology, Program for Structural Biology, Van Andel Research Institute, Grand Rapids MI, USA
⁷State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
⁸Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
⁹Key Laboratory of Molecular Target & Clinical Pharmacology, and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 511436, China
¹⁰Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, Zhejiang 311121, China
These authors contributed equally: Youwen Zhuang, Brian Krumm, Huibing Zhang Correspondence: Bryan L. Roth(bryan_roth@med.unc.edu)Yan Zhang(zhang_yan@zju.edu.cn)H. Eric Xu(Eric.Xu@simm.ac.cn)

Dear Editor,

Dopamine acts as an essential neurotransmitter whose signaling is conducted through five G protein-coupled receptors (GPCRs), dopamine D1 to D5 receptors (DRD1–DRD5).1 The D1-like receptors, comprising DRD1 and DRD5, primarily couple to the Gs family of G proteins to activate adenylyl cyclase and induce cAMP production. DRD1 is the most abundantly expressed dopamine receptor in the CNS.1 It is the central receptor mediating excitatory dopamine signaling in multiple dopaminergic pathways. Dysregulation of DRD1 signaling has been directly linked to Parkinson’s disease (PD), schizophrenia, and drug abuse.1,2 Due to its fundamental functions in human diseases, DRD1 has long been the subject of intensive drug development efforts toward the treatment of neuropsychiatric diseases.3 A majority of DRD1 agonists, including the SKF compounds, targets the orthosteric pocket of DRD1, but none has passed clinical trials for neuropsychiatric symptoms to date.3

https://doi.org/10.1038/s41422-021-00482-0

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