8IRS

Dopamine Receptor D2R-Gi-Rotigotine complex

Summary for 8IRS

• Entry DOI: 10.2210/pdb8irs/pdb
• EMDB information: 35684
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ScFv16, ... (6 entities in total)
• Functional Keywords: dopamine, dopamine receptor, gpcr, d2r, gi, rotigotine, polypharmacology parkinson's disease, restless legs syndrome, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 180207.22

Authors

Xu, P.,Huang, S.,Zhuang, Y.,Mao, C.,Zhang, Y.,Wang, Y.,Li, H.,Jiang, Y.,Zhang, Y.,Xu, H.E. (deposition date: 2023-03-19, release date: 2023-06-07, Last modification date: 2024-11-06)

Primary citation

Xu, P.,Huang, S.,Krumm, B.E.,Zhuang, Y.,Mao, C.,Zhang, Y.,Wang, Y.,Huang, X.P.,Liu, Y.F.,He, X.,Li, H.,Yin, W.,Jiang, Y.,Zhang, Y.,Roth, B.L.,Xu, H.E.
Structural genomics of the human dopamine receptor system.
Cell Res., 33:604-616, 2023

PubMed Abstract: The dopaminergic 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 cryo-EM structures of all five 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 recognition in different dopamine receptors. Structural analysis together with functional assays illuminate determinants of ligand polypharmacology and selectivity. The structures also uncover the mechanisms of dopamine receptor activation, unique structural features among the five receptor subtypes, and the basis of G protein coupling specificity. Our work provides a comprehensive set of structural templates for the rational design of specific ligands to treat CNS diseases targeting the dopaminergic system.

PubMed: 37221270
DOI: 10.1038/s41422-023-00808-0

Experimental method

ELECTRON MICROSCOPY (3 Å)