Structural insights into the human D1 and D2 dopamine receptor signaling complexes

The D1- and D2-dopamine receptors (D1R and D2R), which signal through Gs and Gi, respectively, represent the principal stimulatory and inhibitory dopamine receptors in the central nervous system. D1R and D2R also represent the main therapeutic targets for Parkinson’s disease, schizophrenia, and many other neuropsychiatric disorders, and insight into their signaling is essential for understanding both therapeutic and side effects of dopaminergic drugs. Here, we report four cryoelectron microscopy (cryo-EM) structures of D1R-Gs and D2R-Gi signaling complexes with selective and non-selective dopamine agonists, including two currently used anti-Parkinson’s disease drugs, apomorphine and bromocriptine. These structures, together with mutagenesis studies, reveal the conserved binding mode of dopamine agonists, the unique pocket topology underlying ligand selectivity, the conformational changes in receptor activation, and potential structural determinants for G protein-coupling selectivity. These results provide both a molecular understanding of dopamine signaling and multiple structural templates for drug design targeting the dopaminergic system. [Display omitted] •Structures of dopamine receptor D1R-Gs complexes with three agonists•Structure of dopamine receptor D2R-Gi complex bound to bromocriptine at 2.8 Å resolution•Highly similar structures between the active states of D1R and β2- adrenergic receptor•Structural determinants for ligand and G protein selectivity between D1R and D2R•G-protein biased agonism of SKF83959 toward D1R from structural and functional studies Near-atomic resolution structures of activated D1R-Gs and D2R-Gi signaling complexes, together with multiple functional studies, reveal the conserved catechol agonist binding mode in D1R and the structural basis that underlies D1R and D2R ligand selectivity and G protein-coupling specificity.