TY - JOUR T1 - Structural Genomics of the Human Dopamine Receptor System JF - bioRxiv DO - 10.1101/2022.10.09.511478 SP - 2022.10.09.511478 AU - Peiyu Xu AU - Sijie Huang AU - Brian E. Krumm AU - Youwen Zhuang AU - Chunyou Mao AU - Yumu Zhang AU - Yue Wang AU - Xi-Ping Huang AU - Yong-Feng Liu AU - Xinheng He AU - Huadong Li AU - Wanchao Yin AU - Yi Jiang AU - Yan Zhang AU - Bryan L. Roth AU - H. Eric Xu Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/10/10/2022.10.09.511478.abstract N2 - 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 StatementThe authors have declared no competing interest. ER -