7CMU

Dopamine Receptor D3R-Gi-Pramipexole complex

Summary for 7CMU

• Entry DOI: 10.2210/pdb7cmu/pdb
• EMDB information: 30410
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: g protein-coupled receptor, dopamine receptor, membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 5
• Total formula weight: 173685.30

Authors

Xu, P.,Huang, S.,Mao, C.,Krumm, B.,Zhou, X.,Tan, Y.,Huang, X.-P.,Liu, Y.,Shen, D.-D.,Jiang, Y.,Yu, X.,Jiang, H.,Melcher, K.,Roth, B.,Cheng, X.,Zhang, Y.,Xu, H. (deposition date: 2020-07-29, release date: 2021-03-10, Last modification date: 2024-10-23)

Primary citation

Xu, P.,Huang, S.,Mao, C.,Krumm, B.E.,Zhou, X.E.,Tan, Y.,Huang, X.P.,Liu, Y.,Shen, D.D.,Jiang, Y.,Yu, X.,Jiang, H.,Melcher, K.,Roth, B.L.,Cheng, X.,Zhang, Y.,Xu, H.E.
Structures of the human dopamine D3 receptor-G i complexes.
Mol.Cell, 81:1147-, 2021

PubMed Abstract: 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 G 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.

PubMed: 33548201
DOI: 10.1016/j.molcel.2021.01.003

Experimental method

ELECTRON MICROSCOPY (3 Å)