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- PDB-9t7p: Cryo-EM structure of ESG-2-36-bound D3 dopamine receptor with mini-Go -

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Basic information

Entry
Database: PDB / ID: 9t7p
TitleCryo-EM structure of ESG-2-36-bound D3 dopamine receptor with mini-Go
Components
  • (Guanine nucleotide-binding protein ...) x 2
  • D(3) dopamine receptor,Lgbit
  • Engineered miniGo,Guanine nucleotide-binding protein G(o) subunit alpha,Guanine nucleotide-binding protein G(o) subunit alpha
  • scFv16
KeywordsMEMBRANE PROTEIN / GPCR / agonist
Function / homology
Function and homology information


musculoskeletal movement, spinal reflex action / acid secretion / dopamine neurotransmitter receptor activity, coupled via Gi/Go / response to histamine / regulation of potassium ion transport / Dopamine receptors / regulation of dopamine uptake involved in synaptic transmission / phospholipase C-activating dopamine receptor signaling pathway / positive regulation of dopamine receptor signaling pathway / negative regulation of oligodendrocyte differentiation ...musculoskeletal movement, spinal reflex action / acid secretion / dopamine neurotransmitter receptor activity, coupled via Gi/Go / response to histamine / regulation of potassium ion transport / Dopamine receptors / regulation of dopamine uptake involved in synaptic transmission / phospholipase C-activating dopamine receptor signaling pathway / positive regulation of dopamine receptor signaling pathway / negative regulation of oligodendrocyte differentiation / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / G protein-coupled receptor internalization / G protein-coupled dopamine receptor signaling pathway / negative regulation of synaptic transmission, glutamatergic / arachidonate secretion / response to morphine / dopamine metabolic process / positive regulation of cytokinesis / negative regulation of cytosolic calcium ion concentration / regulation of dopamine secretion / parallel fiber to Purkinje cell synapse / social behavior / negative regulation of insulin secretion / negative regulation of protein secretion / prepulse inhibition / postsynaptic modulation of chemical synaptic transmission / negative regulation of blood pressure / behavioral response to cocaine / adenylate cyclase-inhibiting dopamine receptor signaling pathway / positive regulation of mitotic nuclear division / muscle contraction / visual learning / adenylate cyclase-inhibiting serotonin receptor signaling pathway / learning / G protein-coupled serotonin receptor binding / locomotory behavior / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / circadian regulation of gene expression / response to cocaine / intracellular calcium ion homeostasis / GABA-ergic synapse / G protein-coupled receptor activity / G-protein beta/gamma-subunit complex binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G protein-coupled acetylcholine receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADP signalling through P2Y purinoceptor 1 / cellular response to catecholamine stimulus / G beta:gamma signalling through PI3Kgamma / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / G alpha (12/13) signalling events / G-protein beta-subunit binding / extracellular vesicle / Thrombin signalling through proteinase activated receptors (PARs) / signaling receptor complex adaptor activity / GTPase binding / cell body / G protein activity / presynaptic membrane / Ca2+ pathway / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / G alpha (s) signalling events / G alpha (q) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / Ras protein signal transduction / learning or memory / postsynaptic membrane / Extra-nuclear estrogen signaling / response to xenobiotic stimulus / G protein-coupled receptor signaling pathway / lysosomal membrane
Similarity search - Function
Dopamine D3 receptor / Dopamine receptor family / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / G-protein, gamma subunit ...Dopamine D3 receptor / Dopamine receptor family / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / 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 WD-40 repeat protein / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 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
: / Guanine nucleotide-binding protein G(o) subunit alpha / D(3) 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
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.85 Å
AuthorsYardeni, E.H. / Kiss, D.J. / Keseru, G.M. / Shalev-Benami, M.
Funding supportEuropean Union, 1items
OrganizationGrant numberCountry
European Research Council (ERC)949364European Union
CitationJournal: Sci Adv / Year: 2026
Title: The structure of the dopamine D receptor bound to cariprazine reveals principles for partial agonists with designed pharmacology.
Authors: Eliane Hadas Yardeni / Dóra Judit Kiss / Julie Sanchez / Keshet Shavit / Dénes Szepesi Kovács / Attila Egyed / Caleb D Vogt / Supriya A Gaitonde / Jacqueline Glenn / Meritxell Canals / ...Authors: Eliane Hadas Yardeni / Dóra Judit Kiss / Julie Sanchez / Keshet Shavit / Dénes Szepesi Kovács / Attila Egyed / Caleb D Vogt / Supriya A Gaitonde / Jacqueline Glenn / Meritxell Canals / Michel Bouvier / Amy Hauck Newman / J Robert Lane / György M Keserű / Moran Shalev-Benami /
Abstract: The third-generation antipsychotic cariprazine is a low-efficacy partial agonist of the dopamine D receptor (DR). Here, we report the cryo-electron microscopy structure of cariprazine bound to DR, ...The third-generation antipsychotic cariprazine is a low-efficacy partial agonist of the dopamine D receptor (DR). Here, we report the cryo-electron microscopy structure of cariprazine bound to DR, establishing a framework for understanding ligand recognition in this receptor. We further determine structures of DR in complex with a series of cariprazine derivatives spanning inverse agonists to high-efficacy partial agonists. Integration of structural data with pharmacological profiling and molecular dynamics simulations reveals how subtle chemical modifications translate into distinct functional outcomes. Determinants distinguishing agonism from inverse agonism are well defined, whereas differences among partial agonists arise from small positional shifts of the ligand within the orthosteric binding site. In contrast, the extended binding site primarily modulates ligand stability, affinity, and receptor selectivity. These findings establish a mechanistic link between bitopic ligand architecture and receptor activation, providing a "ligand-centric" view of DR signaling. Leveraging these principles, we designed and validated cariprazine derivatives with enhanced D/D selectivity and partial agonist activity. Together, this work provides a structural and pharmacological blueprint for the rational design of DR-targeting ligands with tailored efficacy and therapeutic profiles.
History
DepositionNov 11, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 9, 2026Provider: repository / Type: Initial release
Revision 1.0Sep 9, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
R: D(3) dopamine receptor,Lgbit
A: Engineered miniGo,Guanine nucleotide-binding protein G(o) subunit alpha,Guanine nucleotide-binding protein G(o) subunit alpha
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
C: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
S: scFv16
hetero molecules


Theoretical massNumber of molelcules
Total (without water)167,7056
Polymers167,2995
Non-polymers4071
Water00
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 , 2 types, 2 molecules RA

#1: Protein D(3) dopamine receptor,Lgbit / Dopamine D3 receptor


Mass: 65118.730 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DRD3 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P35462
#2: Protein Engineered miniGo,Guanine nucleotide-binding protein G(o) subunit alpha,Guanine nucleotide-binding protein G(o) subunit alpha


Mass: 25248.893 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAO1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P09471, Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement

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Guanine nucleotide-binding protein ... , 2 types, 2 molecules BC

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


Mass: 41729.582 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
#4: 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

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Antibody / Non-polymers , 2 types, 2 molecules S

#5: Antibody scFv16


Mass: 27340.482 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm)
#6: Chemical ChemComp-A1JUA / 3-[4-[2-[4-(2-fluoranyl-3-methoxy-phenyl)piperazin-1-yl]ethyl]cyclohexyl]-1,1-dimethyl-urea


Mass: 406.537 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H35FN4O2 / Feature type: SUBJECT OF INVESTIGATION

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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: GPCR-Go protein complex / Type: COMPLEX / Entity ID: #1, #3-#5 / Source: RECOMBINANT
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
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 38.6 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 6543064
3D reconstructionResolution: 2.85 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 113825 / Symmetry type: POINT

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