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- EMDB-52625: Dopamine 1 receptor:GaS complex bound to 24 -

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Basic information

Entry
Database: EMDB / ID: EMD-52625
TitleDopamine 1 receptor:GaS complex bound to 24
Map data
Sample
  • Complex: D1R complex with Gas and 24
    • Protein or peptide: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Beta-2 adrenergic receptor,D(1A) dopamine receptor
  • Ligand: 6-(3-fluoranyl-5-furo[3,2-c]pyridin-4-yloxy-pyridin-2-yl)-1,5-dimethyl-pyrimidine-2,4-dione
  • Ligand: water
KeywordsD1R / GS / AGONIST / PARKINSON / NEUROSCIENCE / D1R GS / HORMONE
Function / homology
Function and homology information


dopamine neurotransmitter receptor activity, coupled via Gs / dopamine neurotransmitter receptor activity / operant conditioning / cerebral cortex GABAergic interneuron migration / Dopamine receptors / dopamine binding / regulation of dopamine uptake involved in synaptic transmission / phospholipase C-activating dopamine receptor signaling pathway / peristalsis / heterotrimeric G-protein binding ...dopamine neurotransmitter receptor activity, coupled via Gs / dopamine neurotransmitter receptor activity / operant conditioning / cerebral cortex GABAergic interneuron migration / Dopamine receptors / dopamine binding / regulation of dopamine uptake involved in synaptic transmission / phospholipase C-activating dopamine receptor signaling pathway / peristalsis / heterotrimeric G-protein binding / modification of postsynaptic structure / G protein-coupled receptor complex / positive regulation of neuron migration / grooming behavior / habituation / regulation of dopamine metabolic process / sensitization / dopamine transport / astrocyte development / dentate gyrus development / striatum development / conditioned taste aversion / positive regulation of potassium ion transport / maternal behavior / arrestin family protein binding / positive regulation of mini excitatory postsynaptic potential / beta2-adrenergic receptor activity / negative regulation of smooth muscle contraction / non-motile cilium / AMPA selective glutamate receptor signaling pathway / positive regulation of autophagosome maturation / norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure / heat generation / norepinephrine binding / long-term synaptic depression / Adrenoceptors / mating behavior / adult walking behavior / positive regulation of lipophagy / negative regulation of multicellular organism growth / negative regulation of G protein-coupled receptor signaling pathway / ciliary membrane / G protein-coupled dopamine receptor signaling pathway / temperature homeostasis / endosome to lysosome transport / response to psychosocial stress / adrenergic receptor signaling pathway / diet induced thermogenesis / D-glucose import / dopamine metabolic process / transmission of nerve impulse / positive regulation of cAMP/PKA signal transduction / adenylate cyclase binding / smooth muscle contraction / PKA activation in glucagon signalling / developmental growth / G-protein alpha-subunit binding / hair follicle placode formation / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / bone resorption / D1 dopamine receptor binding / potassium channel regulator activity / positive regulation of bone mineralization / intracellular transport / neuronal dense core vesicle / prepulse inhibition / positive regulation of synaptic transmission, glutamatergic / brown fat cell differentiation / behavioral fear response / vascular endothelial cell response to laminar fluid shear stress / neuronal action potential / renal water homeostasis / activation of adenylate cyclase activity / Hedgehog 'off' state / intercellular bridge / synapse assembly / adenylate cyclase-activating adrenergic receptor signaling pathway / regulation of sodium ion transport / behavioral response to cocaine / cellular response to glucagon stimulus / presynaptic modulation of chemical synaptic transmission / regulation of insulin secretion / receptor-mediated endocytosis / response to cold / response to amphetamine / adenylate cyclase activator activity / positive regulation of release of sequestered calcium ion into cytosol / trans-Golgi network membrane / synaptic transmission, glutamatergic / negative regulation of inflammatory response to antigenic stimulus / clathrin-coated endocytic vesicle membrane / bone development / G protein-coupled receptor activity / visual learning / GABA-ergic synapse / platelet aggregation / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / memory / cognition / vasodilation
Similarity search - Function
Dopamine D1 receptor / Dopamine receptor family / Beta 2 adrenoceptor / Adrenoceptor family / G-protein alpha subunit, group S / Serpentine type 7TM GPCR chemoreceptor Srsx / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. ...Dopamine D1 receptor / Dopamine receptor family / Beta 2 adrenoceptor / Adrenoceptor family / G-protein alpha subunit, group S / Serpentine type 7TM GPCR chemoreceptor Srsx / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Beta-2 adrenergic receptor / D(1A) dopamine receptor / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.72 Å
AuthorsClairfeuille T / Rodriguez Sarmiento RM
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: J Med Chem / Year: 2025
Title: Orally Bioavailable Dopamine D1/D5 Receptor-Biased Agonists to Study the Role of β-Arrestin in Treatment-Related Dyskinesia in Parkinson's Disease.
Authors: Rosa María Rodríguez Sarmiento / Stefan Berchtold / Nenad Manevski / Lothar Lindemann / Fabian Dey / Thomas Clairfeuille / Davide Amendola / Nicolas Vautrelle / Venceslas Duveau / Eoin C O Connor /
Abstract: Dopamine replacement therapies for Parkinson's disease often produce dyskinesias with long-term use. Published studies suggest that introducing β-arrestin signaling might be protective for ...Dopamine replacement therapies for Parkinson's disease often produce dyskinesias with long-term use. Published studies suggest that introducing β-arrestin signaling might be protective for dyskinesia. We advanced known noncatecholamine D1/D5 receptor G protein-biased agonists and found that removal of oxygen in the linker from published compounds limited β-arrestin recruitment, whereas introduction of nitrogen on the central -phenyl linker favored β-arrestin recruitment and provided orally bioavailable compounds. Cryogenic electron microscopy suggested key receptor-ligand interactions influencing the different bias behaviors. We discovered compound , a D1/D5 receptor agonist with β-arrestin recruitment and properties for use . We compared with tavapadon, which shows weak efficacy for β-arrestin signaling, in a rat model of Parkinson's disease with L-DOPA-induced dyskinesias. At particular doses, compound produced efficacy comparable to L-DOPA, but with fewer concomitant dyskinesias. This first study suggests that β-arrestin may have a positive influence on reducing dyskinesias following acute administration.
History
DepositionJan 27, 2025-
Header (metadata) releaseJul 16, 2025-
Map releaseJul 16, 2025-
UpdateJul 23, 2025-
Current statusJul 23, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_52625.png

Downloads & links

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Map

FileDownload / File: emd_52625.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.93 Å/pix.
x 288 pix.
= 268.992 Å		0.93 Å/pix.
x 288 pix.
= 268.992 Å		0.93 Å/pix.
x 288 pix.
= 268.992 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.934 Å
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Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.8917366 - 1.456908
Average (Standard dev.)-0.00013875305 (±0.020705044)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 268.992 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_52625_msk_1.map
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Additional map: #1

Fileemd_52625_additional_1.map
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Half map: #2

Fileemd_52625_half_map_1.map
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Half map: #1

Fileemd_52625_half_map_2.map
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Sample components

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Entire : D1R complex with Gas and 24

EntireName: D1R complex with Gas and 24
Components
  • Complex: D1R complex with Gas and 24
    • Protein or peptide: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Beta-2 adrenergic receptor,D(1A) dopamine receptor
  • Ligand: 6-(3-fluoranyl-5-furo[3,2-c]pyridin-4-yloxy-pyridin-2-yl)-1,5-dimethyl-pyrimidine-2,4-dione
  • Ligand: water

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Supramolecule #1: D1R complex with Gas and 24

SupramoleculeName: D1R complex with Gas and 24 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short

MacromoleculeName: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
EC number: Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 45.755547 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKSTIVKQM RILHVNGFNG EGGEEDPQAA RSNSDGEKA TKVQDIKNNL KEAIETIVAA MSNLVPPVEL ANPENQFRVD YILSVMNVPD FDFPPEFYEH AKALWEDEGV R ACYERSNE ...String:
MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKSTIVKQM RILHVNGFNG EGGEEDPQAA RSNSDGEKA TKVQDIKNNL KEAIETIVAA MSNLVPPVEL ANPENQFRVD YILSVMNVPD FDFPPEFYEH AKALWEDEGV R ACYERSNE YQLIDCAQYF LDKIDVIKQA DYVPSDQDLL RCRVLTSGIF ETKFQVDKVN FHMFDVGAQR DERRKWIQCF ND VTAIIFV VASSSYNMVI REDNQTNRLQ EALNLFKSIW NNRWLRTISV ILFLNKQDLL AEKVLAGKSK IEDYFPEFAR YTT PEDATP EPGEDPRVTR AKYFIRDEFL RISTASGDGR HYCYPHFTCS VDTENIRRVF NDCRDIIQRM HLRQYELL

UniProtKB: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short

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Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 38.636199 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGHHHHHHHH SELDQLRQEA EQLKNQIRDA RKACADATLS QITNNIDPVG RIQMRTRRTL RGHLAKIYAM HWGTDSRLLV SASQDGKLI IWDSYTTNKV HAIPLRSSWV MTCAYAPSGN YVACGGLDNI CSIYNLKTRE GNVRVSRELA GHTGYLSCCR F LDDNQIVT ...String:
MGHHHHHHHH SELDQLRQEA EQLKNQIRDA RKACADATLS QITNNIDPVG RIQMRTRRTL RGHLAKIYAM HWGTDSRLLV SASQDGKLI IWDSYTTNKV HAIPLRSSWV MTCAYAPSGN YVACGGLDNI CSIYNLKTRE GNVRVSRELA GHTGYLSCCR F LDDNQIVT SSGDTTCALW DIETGQQTTT FTGHTGDVMS LSLAPDTRLF VSGACDASAK LWDVREGMCR QTFTGHESDI NA ICFFPNG NAFATGSDDA TCRLFDLRAD QELMTYSHDN IICGITSVSF SKSGRLLLAG YDDFNCNVWD ALKADRAGVL AGH DNRVSC LGVTDDGMAV ATGSWDSFLK IWNG

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Macromolecule #4: Beta-2 adrenergic receptor,D(1A) dopamine receptor

MacromoleculeName: Beta-2 adrenergic receptor,D(1A) dopamine receptor / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 59.074711 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MDSKGSSQKG SRLLLLLVVS NLLLCQGVVS DYKDDDDKDM GQPGNGSAFL LAPNGSHAPD HDVTQERDEG GSENLYFQGG GSMRTLNTS AMDGTGLVVE RDFSVRILTA CFLSLLILST LLGNTLVCAA VIRFRHLRSK VTNFFVISLA VSDLLVAVLV M PWKAVAEI ...String:
MDSKGSSQKG SRLLLLLVVS NLLLCQGVVS DYKDDDDKDM GQPGNGSAFL LAPNGSHAPD HDVTQERDEG GSENLYFQGG GSMRTLNTS AMDGTGLVVE RDFSVRILTA CFLSLLILST LLGNTLVCAA VIRFRHLRSK VTNFFVISLA VSDLLVAVLV M PWKAVAEI AGFWPFGSFC NIWVAFDIMC STASILNLCV ISVDRYWAIS SPFRYERKMT PKAAFILISV AWTLSVLISF IP VQLSWHK AKPTSPSDGN ATSLAETIDN CDSSLSRTYA ISSSVISFYI PVAIMIVTYT RIYRIAQKQI RRIAALERAA VHA KNCQTT TGNGKPVECS QPESSFKMSF KRETKVLKTL SVIMGVFVCC WLPFFILNCI LPFCGSGETQ PFCIDSNTFD VFVW FGWAN SSLNPIIYAF NADFRKAFST LLGCYRLCPA TNNAIETVSI NNNGAAMFSS HHEPRGSISK ECNLVYLIPH AVGSS EDLK KEEAAGIARP LEKLSPALSV ILDYDTDVSL EKIQPITQNG QHPTHHHHHH HH

UniProtKB: Beta-2 adrenergic receptor, D(1A) dopamine receptor

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Macromolecule #5: 6-(3-fluoranyl-5-furo[3,2-c]pyridin-4-yloxy-pyridin-2-yl)-1,5-dim...

MacromoleculeName: 6-(3-fluoranyl-5-furo[3,2-c]pyridin-4-yloxy-pyridin-2-yl)-1,5-dimethyl-pyrimidine-2,4-dione
type: ligand / ID: 5 / Number of copies: 1 / Formula: A1IZV
Molecular weightTheoretical: 368.319 Da

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Macromolecule #6: water

MacromoleculeName: water / type: ligand / ID: 6 / Number of copies: 2 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 283 K / Instrument: LEICA PLUNGER

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Electron microscopy

MicroscopeJEOL CRYO ARM 300
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 2.72 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.4) / Number images used: 685808
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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