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Structures of the human dopamine D3 receptor-Gi complexes
Peiyu Xu1, Sijie Huang2, Chunyou Mao3
1Department of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Molecular Cell
|February 6, 2021
Summary
Structural insights into dopamine D3 receptor activation by agonists PD128907 and pramipexole were revealed using cryo-EM. These findings provide a basis for developing novel treatments for central nervous system diseases targeting the dopamine system.
Area of Science:
- Neuroscience
- Structural Biology
- Pharmacology
Background:
- The dopamine system, comprising five dopamine receptors (D1R-D5R), is crucial for central nervous system (CNS) function.
- Ligands targeting dopamine receptors are vital for treating neuropsychiatric disorders.
Purpose of the Study:
- To elucidate the structural basis of dopamine D3 receptor (D3R) activation by agonists.
- To provide structural templates for the development of CNS-targeting drugs.
Main Methods:
- Cryo-electron microscopy (cryo-EM) was used to determine the structures of human D3R.
- Structures were obtained in complex with an inhibitory G protein and bound to D3R-selective agonists PD128907 and pramipexole.
- Mutagenesis and homology modeling were employed to investigate ligand specificity and G protein coupling.
Main Results:
- Two cryo-EM structures of human D3R bound to agonists PD128907 and pramipexole were determined.
- Agonist binding modes distinct from antagonist-bound structures were observed.
- Conformational signatures of ligand-induced receptor activation and determinants of ligand specificity were identified.
Conclusions:
- The study reveals the structural mechanisms underlying agonist binding and activation of the dopamine D3 receptor.
- The findings provide critical structural insights for designing specific ligands targeting the dopaminergic system for CNS diseases.
- The research offers a foundation for developing novel therapeutics for conditions like Parkinson's disease.
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