Structural genomics of the human dopamine receptor system

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 rep...

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Published in:Cell research 2023-08, Vol.33 (8), p.604-616
Main Authors: Xu, Peiyu, Huang, Sijie, Krumm, Brian E., Zhuang, Youwen, Mao, Chunyou, Zhang, Yumu, Wang, Yue, Huang, Xi-Ping, Liu, Yong-Feng, He, Xinheng, Li, Huadong, Yin, Wanchao, Jiang, Yi, Zhang, Yan, Roth, Bryan L., Xu, H. Eric
Format: Article
Language:English
Subjects:
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Biomedical and Life Sciences
Brain research
Cell Biology
Central nervous system
Dopamine
Dopamine - metabolism
Dopamine - therapeutic use
Dopamine D1 receptors
Dopamine D5 receptors
Dopamine receptors
Drugs
Genomics
Hospitals
Humans
Life Sciences
Ligands
Medicine
Mental disorders
Movement disorders
Nervous system
Neurodegenerative diseases
Parkinson Disease - drug therapy
Parkinson Disease - genetics
Parkinson's disease
Pharmacology
Proteins
Receptor mechanisms
Receptors
Receptors, Dopamine - metabolism
Restless legs syndrome
Schizophrenia
Science
Structural analysis
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Summary: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.
ISSN:1748-7838
1001-0602
1748-7838
DOI:10.1038/s41422-023-00808-0