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- PDB-31bg: Cryo-EM structure of Dopamine 3 receptor:Go complex bound to bito... -

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Basic information

Entry
Database: PDB / ID: 31bg
TitleCryo-EM structure of Dopamine 3 receptor:Go complex bound to bitopic AB13-46A
Components
  • Green fluorescent protein,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
  • Guanine nucleotide-binding protein G(o) subunit alpha
KeywordsMEMBRANE PROTEIN / Bitopic molecules / dopamine receptor / drug selectivity / structure-based drug design / GPCRs / G protein-coupled receptors / ligand-triggered receptor conformation
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 / adenylate cyclase-inhibiting dopamine receptor signaling pathway / Dopamine receptors / regulation of dopamine uptake involved in synaptic transmission / phospholipase C-activating dopamine receptor signaling pathway / positive regulation of dopamine receptor signaling pathway ...musculoskeletal movement, spinal reflex action / acid secretion / dopamine neurotransmitter receptor activity, coupled via Gi/Go / response to histamine / regulation of potassium ion transport / adenylate cyclase-inhibiting dopamine receptor signaling pathway / 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 activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor / Sensory perception of sweet, bitter, and umami (glutamate) taste / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Ca2+ pathway / G alpha (z) signalling events / G protein-coupled dopamine receptor signaling pathway / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G protein-coupled receptor internalization / Vasopressin regulates renal water homeostasis via Aquaporins / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / negative regulation of synaptic transmission, glutamatergic / G alpha (q) signalling events / G alpha (i) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / arachidonate secretion / photoreceptor outer segment membrane / response to morphine / spectrin binding / dopamine metabolic process / positive regulation of cytokinesis / negative regulation of cytosolic calcium ion concentration / sensory perception of taste / alkylglycerophosphoethanolamine phosphodiesterase activity / retina development in camera-type eye / parallel fiber to Purkinje cell synapse / regulation of dopamine secretion / social behavior / negative regulation of insulin secretion / negative regulation of protein secretion / cardiac muscle cell apoptotic process / photoreceptor outer segment / prepulse inhibition / postsynaptic modulation of chemical synaptic transmission / negative regulation of blood pressure / behavioral response to cocaine / positive regulation of mitotic nuclear division / photoreceptor inner segment / muscle contraction / visual learning / learning / adenylate cyclase-inhibiting serotonin receptor signaling pathway / G protein-coupled serotonin receptor binding / locomotory behavior / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / bioluminescence / circadian regulation of gene expression / response to cocaine / generation of precursor metabolites and energy / intracellular calcium ion homeostasis / cell population proliferation / 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 / phospholipase C-activating G protein-coupled 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 / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / 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
Similarity search - Function
Dopamine D3 receptor / Dopamine receptor family / Green fluorescent protein, GFP / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / G protein alpha subunit, helical insertion / G protein alpha subunit ...Dopamine D3 receptor / Dopamine receptor family / Green fluorescent protein, GFP / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / 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 / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / 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 / Green fluorescent protein / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Rattus norvegicus (Norway rat)
Aequorea victoria (jellyfish)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.47 Å
AuthorsArroyo-Urea, S. / Garcia-Nafria, J.
Funding support Spain, 2items
OrganizationGrant numberCountry
Ministerio de Ciencia e Innovacion (MCIN)PID2020-113359GA-I00 Spain
Ministerio de Ciencia e Innovacion (MCIN)PID2023-148739NB-I00 Spain
CitationJournal: JACS Au / Year: 2026
Title: A Ligand-Triggered Receptor Conformation Enables the Design of Selective Agonists for the Dopamine 3 Receptor (DR) Using a Bitopic Strategy.
Authors: Sandra Arroyo-Urea / Antonina L Nazarova / Alexander Knieb / Hawau Abdulsalam / Khorshada Jahan / Ting Du / Song Gao / Amy Hauck Newman / Vsevolod Katritch / Javier García-Nafría / Alessandro Bonifazi /
Abstract: While G protein-coupled receptors (GPCRs) represent the largest drug target family, designing subtype-selective molecules is still a challenge, especially to distinguish among closely related ...While G protein-coupled receptors (GPCRs) represent the largest drug target family, designing subtype-selective molecules is still a challenge, especially to distinguish among closely related subtypes. One of the most challenging cases is the distinction between dopamine DR and DR, pivotal receptors in motor functions and cognition, and targets of Parkinson's disease treatments, schizophrenia, or substance use disorders. Attempts to design DR-selective molecules with ligands binding toward the first transmembrane helix (the most sequence-diverse and conformationally flexible segment in GPCRs but rarely participating in ligand binding) allowed us to discover a ligand-induced ordering of TM1 unique to DR, yielding an unexploited selectivity site for drug development. Using rational bitopic drug design and the ligand-triggered conformation of the DR we designed, synthesized, and characterized the most selective DR agonists to date, >100,000-fold more selective than available ligands. More specifically, we report DR partial agonists AB12-82 () and AB13-73A (), with >575,000- and >750,000-fold subtype selectivity, picomolar potency, and 85% and 49% efficacy, respectively. We also present the most selective full agonists reported to date, AB13-08 () and AB13-46A (), presenting low and subnanomolar potencies with >2,800- and 6,300-fold selectivity for DR. Overall, we introduce a first-in-class pharmacological toolbox to dissect the (patho)-physiology of DR, open new avenues for the design of improved neurotherapeutics, and show that using ligand-induced TM1 reorganizations might represent a promising strategy for the design of subtype-selective molecules in other GPCRs.
History
DepositionMay 22, 2026Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 19, 2026Provider: repository / Type: Initial release
Revision 1.0Aug 19, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Aug 19, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Aug 19, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Aug 19, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Aug 19, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: 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
R: Green fluorescent protein,D(3) dopamine receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)162,4575
Polymers161,9934
Non-polymers4641
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

#1: Protein Guanine nucleotide-binding protein G(o) subunit alpha


Mass: 40097.438 Da / Num. of mol.: 1 / Mutation: S47N, G204A, E246A, M249K, A326S, K54E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAO1 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: P09471, Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 39373.992 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: His-Gbeta-1 / Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: GNB1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P54311
#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: Trichoplusia ni (cabbage looper) / References: UniProt: P59768
#4: Protein Green fluorescent protein,D(3) dopamine receptor / Dopamine D3 receptor


Mass: 74660.891 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R
Source: (gene. exp.) Aequorea victoria (jellyfish), (gene. exp.) Homo sapiens (human)
Gene: GFP, DRD3 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P42212, UniProt: P35462
#5: Chemical ChemComp-A1J83 / ~{N}-[2-[(1~{R},2~{S})-2-[[(2~{S},5~{S})-2-(6-azanylpyridin-3-yl)-5-methyl-morpholin-4-yl]methyl]cyclopropyl]ethyl]-6-methoxy-1~{H}-indole-2-carboxamide


Mass: 463.572 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H33N5O3 / Feature type: SUBJECT OF INVESTIGATION
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: Dopamine 3 Receptor:Go complex bound to bitopic AB13-46A
Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.4
SpecimenConc.: 2.8 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid type: Quantifoil R1/1
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 %

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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: 3000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 52.3 e/Å2 / Film or detector model: GATAN K3 BIOCONTINUUM (6k x 4k) / Num. of real images: 13180

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Processing

EM software
IDNameVersionCategory
1RELION5particle selection
2cryoSPARCv4particle selection
5RELION5CTF correction
8Coot0.9.6.2model fitting
12cryoSPARCv4classification
13cryoSPARC3D reconstruction
20PHENIX2model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.47 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 120394 / Symmetry type: POINT

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