Structural Genomics of the Human Dopamine Receptor System

The dopamine 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 five cryo-EM structures of all 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 binding modes to different dopamine receptors. Structural analysis together with functional assays illuminate determinants of ligand polypharmacology and selectivity. The structures also uncover the mechanisms of the dopamine receptor activation, unique structural features among the five receptor subtypes, and the basis of G-protein coupling specificity. Our works provide a comprehensive set of structural templates for the rational design of specific ligands to treat CNS diseases targeting the dopaminergic system. ### Competing Interest Statement The authors have declared no competing interest.