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TitleLigand recognition and biased agonism of the D1 dopamine receptor.
Journal, issue, pagesNat Commun, Vol. 13, Issue 1, Page 3186, Year 2022
Publish dateJun 8, 2022
AuthorsXiao Teng / Sijia Chen / Yingying Nie / Peng Xiao / Xiao Yu / Zhenhua Shao / Sanduo Zheng /
PubMed AbstractDopamine receptors are widely distributed in the central nervous system and are important therapeutic targets for treatment of various psychiatric and neurological diseases. Here, we report three ...Dopamine receptors are widely distributed in the central nervous system and are important therapeutic targets for treatment of various psychiatric and neurological diseases. Here, we report three cryo-electron microscopy structures of the D1 dopamine receptor (D1R)-Gs complex bound to two agonists, fenoldopam and tavapadon, and a positive allosteric modulator LY3154207. The structure reveals unusual binding of two fenoldopam molecules, one to the orthosteric binding pocket (OBP) and the other to the extended binding pocket (EBP). In contrast, one elongated tavapadon molecule binds to D1R, extending from OBP to EBP. Moreover, LY3154207 stabilizes the second intracellular loop of D1R in an alpha helical conformation to efficiently engage the G protein. Through a combination of biochemical, biophysical and cellular assays, we further show that the broad conformation stabilized by two fenoldopam molecules and interaction between TM5 and the agonist are important for biased signaling of D1R.
External linksNat Commun / PubMed:35676276 / PubMed Central
MethodsEM (single particle)
Resolution3.0 - 3.3 Å
Structure data

EMDB-32964, PDB-7x2c:
Cryo-EM structure of the fenoldopam-bound D1 dopamine receptor and mini-Gs complex
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-32965, PDB-7x2d:
Cryo-EM structure of the tavapadon-bound D1 dopamine receptor and mini-Gs complex
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-32966, PDB-7x2f:
Cryo-EM structure of the dopamine and LY3154207-bound D1 dopamine receptor and mini-Gs complex
Method: EM (single particle) / Resolution: 3.0 Å

Chemicals

ChemComp-CLR:
CHOLESTEROL

ChemComp-G3C:
(1R)-6-chloranyl-1-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol

ChemComp-86W:
1,5-dimethyl-6-[2-methyl-4-[3-(trifluoromethyl)pyridin-2-yl]oxy-phenyl]pyrimidine-2,4-dione / agonist*YM

ChemComp-G4C:
2-[2,6-bis(chloranyl)phenyl]-1-[(1S,3R)-3-(hydroxymethyl)-1-methyl-5-(3-methyl-3-oxidanyl-butyl)-3,4-dihydro-1H-isoquinolin-2-yl]ethanone

ChemComp-LDP:
L-DOPAMINE / medication*YM

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsSIGNALING PROTEIN / GPCR / dopamine receptor / mini-Gs / membrane protein / tavapadon

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