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- PDB-9i52: Dopamine 1 receptor:GaS complex bound to 19B -

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Basic information

Entry
Database: PDB / ID: 9i52
TitleDopamine 1 receptor:GaS complex bound to 19B
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Beta-2 adrenergic receptor,D(1A) dopamine receptor
KeywordsHORMONE / D1R / GS / AGONIST / PARKINSON / NEUROSCIENCE / D1R GS
Function / homology
Function and homology information


dopamine neurotransmitter receptor activity, coupled via Gs / dopamine neurotransmitter receptor activity / cerebral cortex GABAergic interneuron migration / operant conditioning / 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 / cerebral cortex GABAergic interneuron migration / operant conditioning / 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 / regulation of dopamine metabolic process / grooming behavior / positive regulation of neuron migration / habituation / sensitization / dopamine transport / astrocyte development / dentate gyrus development / conditioned taste aversion / striatum development / positive regulation of potassium ion transport / maternal behavior / arrestin family protein binding / positive regulation of mini excitatory postsynaptic potential / beta2-adrenergic receptor activity / AMPA selective glutamate receptor signaling pathway / negative regulation of smooth muscle contraction / non-motile cilium / norepinephrine binding / positive regulation of autophagosome maturation / long-term synaptic depression / norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure / heat generation / Adrenoceptors / mating behavior / adult walking behavior / positive regulation of lipophagy / G protein-coupled dopamine receptor signaling pathway / negative regulation of G protein-coupled receptor signaling pathway / negative regulation of multicellular organism growth / ciliary membrane / temperature homeostasis / adrenergic receptor signaling pathway / endosome to lysosome transport / response to psychosocial stress / diet induced thermogenesis / D-glucose import / neuronal dense core vesicle / dopamine metabolic process / transmission of nerve impulse / positive regulation of cAMP/PKA signal transduction / adenylate cyclase binding / PKA activation in glucagon signalling / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / smooth muscle contraction / developmental growth / hair follicle placode formation / behavioral fear response / G-protein alpha-subunit binding / D1 dopamine receptor binding / bone resorption / positive regulation of bone mineralization / potassium channel regulator activity / prepulse inhibition / intracellular transport / vascular endothelial cell response to laminar fluid shear stress / brown fat cell differentiation / renal water homeostasis / neuronal action potential / behavioral response to cocaine / Hedgehog 'off' state / intercellular bridge / regulation of sodium ion transport / activation of adenylate cyclase activity / synapse assembly / adenylate cyclase-activating adrenergic receptor signaling pathway / presynaptic modulation of chemical synaptic transmission / response to amphetamine / regulation of insulin secretion / cellular response to glucagon stimulus / receptor-mediated endocytosis / positive regulation of synaptic transmission, glutamatergic / adenylate cyclase activator activity / response to cold / positive regulation of release of sequestered calcium ion into cytosol / trans-Golgi network membrane / synaptic transmission, glutamatergic / GABA-ergic synapse / negative regulation of inflammatory response to antigenic stimulus / clathrin-coated endocytic vesicle membrane / G protein-coupled receptor activity / visual learning / bone development / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / memory / G-protein beta/gamma-subunit complex binding / platelet aggregation / Olfactory Signaling Pathway
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 / 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 / WD domain, G-beta 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsClairfeuille, T. / Rodriguez Sarmiento, R.M.
Funding support1items
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, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 16, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
R: Beta-2 adrenergic receptor,D(1A) dopamine receptor
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
A: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
hetero molecules


Theoretical massNumber of molelcules
Total (without water)151,6745
Polymers151,3284
Non-polymers3461
Water362
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein , 1 types, 1 molecules R

#1: Protein Beta-2 adrenergic receptor,D(1A) dopamine receptor / Beta-2 adrenoreceptor / Beta-2 adrenoceptor / Dopamine D1 receptor


Mass: 59074.711 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ADRB2, ADRB2R, B2AR, DRD1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P07550, UniProt: P21728

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules BGA

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


Mass: 38636.199 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768
#4: Protein Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Adenylate cyclase-stimulating G alpha protein


Mass: 45755.547 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAS, GNAS1, GSP / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P63092, Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement

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Non-polymers , 2 types, 3 molecules

#5: Chemical ChemComp-A1IZU / 6-(4-imidazo[1,2-a]pyridin-8-yl-2-methyl-phenyl)-1,5-dimethyl-pyrimidine-2,4-dione


Mass: 346.383 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H18N4O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: D1R complex with Gas and 19B / Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: LEICA PLUNGER / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 283 K

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Electron microscopy imaging

MicroscopyModel: JEOL CRYO ARM 300
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.4particle selection
2PHENIX1.21.1_5286model refinement
13cryoSPARC4.43D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 936735 / Symmetry type: POINT
RefinementHighest resolution: 2.8 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0037444
ELECTRON MICROSCOPYf_angle_d0.45810085
ELECTRON MICROSCOPYf_dihedral_angle_d4.6541027
ELECTRON MICROSCOPYf_chiral_restr0.0411139
ELECTRON MICROSCOPYf_plane_restr0.0041279

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