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TitleStructural genomics of the human dopamine receptor system.
Journal, issue, pagesCell Res, Vol. 33, Issue 8, Page 604-616, Year 2023
Publish dateMay 23, 2023
AuthorsPeiyu Xu / Sijie Huang / Brian E Krumm / Youwen Zhuang / Chunyou Mao / Yumu Zhang / Yue Wang / Xi-Ping Huang / Yong-Feng Liu / Xinheng He / Huadong Li / Wanchao Yin / Yi Jiang / Yan Zhang / Bryan L Roth / H Eric Xu /
PubMed AbstractThe 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 ...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.
External linksCell Res / PubMed:37221270 / PubMed Central
MethodsEM (single particle)
Resolution2.7 - 3.2 Å
Structure data

35683

8irr

EMDB-35683, PDB-8irr:
Dopamine Receptor D1R-Gs-Rotigotine complex
Method: EM (single particle) / Resolution: 3.2 Å

35684

8irs

EMDB-35684, PDB-8irs:
Dopamine Receptor D2R-Gi-Rotigotine complex
Method: EM (single particle) / Resolution: 3.0 Å

35685

8irt

EMDB-35685, PDB-8irt:
Dopamine Receptor D3R-Gi-Rotigotine complex
Method: EM (single particle) / Resolution: 2.7 Å

35686

8iru

EMDB-35686, PDB-8iru:
Dopamine Receptor D4R-Gi-Rotigotine complex
Method: EM (single particle) / Resolution: 3.2 Å

35687

8irv

EMDB-35687, PDB-8irv:
Dopamine Receptor D5R-Gs-Rotigotine complex
Method: EM (single particle) / Resolution: 3.1 Å

Chemicals

ChemComp-R5F:
Rotigotine

ChemComp-CLR:
CHOLESTEROL / Cholesterol

ChemComp-HOH:
WATER / Water

ChemComp-PLM:
PALMITIC ACID / Palmitic acid

Source
  • homo sapiens (human)
  • lama glama (llama)
  • mus musculus (house mouse)
  • escherichia coli (E. coli)
KeywordsMEMBRANE PROTEIN / Dopamine / Dopamine receptor / GPCR / D1R / Gs / Rotigotine / Parkinson's disease / Restless legs syndrome / D2R / Gi / Polypharmacology Parkinson's disease / D3R / D4R / D5R

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