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TitleStructures of the human dopamine D3 receptor-G complexes.
Journal, issue, pagesMol Cell, Vol. 81, Issue 6, Page 1147-11159.e4, Year 2021
Publish dateMar 18, 2021
AuthorsPeiyu Xu / Sijie Huang / Chunyou Mao / Brian E Krumm / X Edward Zhou / Yangxia Tan / Xi-Ping Huang / Yongfeng Liu / Dan-Dan Shen / Yi Jiang / Xuekui Yu / Hualiang Jiang / Karsten Melcher / Bryan L Roth / Xi Cheng / Yan Zhang / H Eric Xu /
PubMed AbstractThe 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 ...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.
External linksMol Cell / PubMed:33548201
MethodsEM (single particle)
Resolution2.7 - 3.0 Å
Structure data

30410

7cmu

EMDB-30410, PDB-7cmu:
Dopamine Receptor D3R-Gi-Pramipexole complex
Method: EM (single particle) / Resolution: 3.0 Å

30411

7cmv

EMDB-30411, PDB-7cmv:
Dopamine Receptor D3R-Gi-PD128907 complex
Method: EM (single particle) / Resolution: 2.7 Å

Chemicals

ChemComp-G6L:
(6S)-N6-propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine / medication*YM

ChemComp-G6O:
(4aR,10bR)-4-propyl-3,4a,5,10b-tetrahydro-2H-chromeno[4,3-b][1,4]oxazin-9-ol

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
  • escherichia coli (E. coli)
KeywordsMEMBRANE PROTEIN / G protein-coupled receptor / Dopamine receptor

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