Molecular Cell
Volume 81, Issue 6, 18 March 2021, Pages 1147-1159.e4
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Article
Structures of the human dopamine D3 receptor-Gi complexes

https://doi.org/10.1016/j.molcel.2021.01.003Get rights and content
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Highlights

  • Structures of dopamine receptor D3R with agonists pramipexole and PD128907

  • Different binding modes of agonists with similar pharmacological properties to D3R

  • Conformational changes associated with D3R activation and selective G protein coupling

  • Selective mechanism of agonists to D3R versus D2R and D4R

Summary

The dopamine system, including five dopamine receptors (D1R–D5R), plays essential roles in the central nervous system (CNS), and ligands that activate dopamine receptors have been used to treat many neuropsychiatric disorders. Here, we report two cryo-EM structures of human D3R in complex with an inhibitory G protein and bound to the D3R-selective agonists PD128907 and pramipexole, the latter of which is used to treat patients with Parkinson’s disease. The structures reveal agonist binding modes distinct from the antagonist-bound D3R structure and conformational signatures for ligand-induced receptor activation. Mutagenesis and homology modeling illuminate determinants of ligand specificity across dopamine receptors and the mechanisms for Gi protein coupling. Collectively our work reveals the basis of agonist binding and ligand-induced receptor activation and provides structural templates for designing specific ligands to treat CNS diseases targeting the dopaminergic system.

Keywords

GPCR
dopamine receptor
D3R
signaling complex
cryo-EM structure
Parkinson’s disease
pramipexole
dopamine receptor activation
G protein selectivity
ligand selectivity

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