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- PDB-9f34: Cryo-EM structure of Dopamine 3 receptor:Go complex bound to bito... -

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Entry
Database: PDB / ID: 9f34
TitleCryo-EM structure of Dopamine 3 receptor:Go complex bound to bitopic FOB02-04A - Conformation B
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Antibody scFv16
  • Green fluorescent protein,D(3) dopamine receptor
KeywordsMEMBRANE PROTEIN / GPCR / complex / bitopic
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 / positive regulation of dopamine receptor signaling pathway / phospholipase C-activating 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 / positive regulation of dopamine receptor signaling pathway / phospholipase C-activating dopamine receptor signaling pathway / negative regulation of oligodendrocyte differentiation / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / negative regulation of synaptic transmission, glutamatergic / G protein-coupled receptor internalization / 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 / Ca2+ pathway / 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 / G alpha (z) signalling events / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / vesicle docking involved in exocytosis / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / response to morphine / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (i) signalling events / alkylglycerophosphoethanolamine phosphodiesterase activity / photoreceptor outer segment membrane / arachidonate secretion / G protein-coupled dopamine receptor signaling pathway / regulation of heart contraction / spectrin binding / regulation of dopamine secretion / negative regulation of cytosolic calcium ion concentration / dopamine metabolic process / adenylate cyclase-activating adrenergic receptor signaling pathway / positive regulation of cytokinesis / behavioral response to cocaine / social behavior / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / photoreceptor outer segment / negative regulation of protein secretion / negative regulation of insulin secretion / prepulse inhibition / G protein-coupled serotonin receptor binding / muscle contraction / cardiac muscle cell apoptotic process / negative regulation of blood pressure / photoreceptor inner segment / positive regulation of mitotic nuclear division / G-protein beta/gamma-subunit complex binding / bioluminescence / learning / generation of precursor metabolites and energy / response to cocaine / locomotory behavior / G protein-coupled receptor activity / circadian regulation of gene expression / visual learning / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Glucagon signaling in metabolic regulation / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G beta:gamma signalling through CDC42 / Vasopressin regulates renal water homeostasis via Aquaporins / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Glucagon-type ligand receptors / G alpha (z) signalling events / Adrenaline,noradrenaline inhibits insulin secretion / intracellular calcium ion homeostasis / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / GPER1 signaling / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / signaling receptor complex adaptor activity
Similarity search - Function
Dopamine D3 receptor / Dopamine receptor family / Green fluorescent protein, GFP / G-protein alpha subunit, group I / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion ...Dopamine D3 receptor / Dopamine receptor family / Green fluorescent protein, GFP / G-protein alpha subunit, group I / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G protein alpha subunit / G-protein alpha subunit / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / 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. / WD domain, G-beta repeat / 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)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.09 Å
AuthorsArroyo-Urea, S. / Garcia-Nafria, J.
Funding support Spain, 1items
OrganizationGrant numberCountry
Ministerio de Ciencia e Innovacion (MCIN)PID2020-113359GA-I00 Spain
CitationJournal: Nat Commun / Year: 2024
Title: A bitopic agonist bound to the dopamine 3 receptor reveals a selectivity site.
Authors: Sandra Arroyo-Urea / Antonina L Nazarova / Ángela Carrión-Antolí / Alessandro Bonifazi / Francisco O Battiti / Jordy Homing Lam / Amy Hauck Newman / Vsevolod Katritch / Javier García-Nafría /
Abstract: Although aminergic GPCRs are the target for ~25% of approved drugs, developing subtype selective drugs is a major challenge due to the high sequence conservation at their orthosteric binding site. ...Although aminergic GPCRs are the target for ~25% of approved drugs, developing subtype selective drugs is a major challenge due to the high sequence conservation at their orthosteric binding site. Bitopic ligands are covalently joined orthosteric and allosteric pharmacophores with the potential to boost receptor selectivity and improve current medications by reducing off-target side effects. However, the lack of structural information on their binding mode impedes rational design. Here we determine the cryo-EM structure of the hDR:Gαβγ complex bound to the DR selective bitopic agonist FOB02-04A. Structural, functional and computational analyses provide insights into its binding mode and point to a new TM2-ECL1-TM1 region, which requires the N-terminal ordering of TM1, as a major determinant of subtype selectivity in aminergic GPCRs. This region is underexploited in drug development, expands the established secondary binding pocket in aminergic GPCRs and could potentially be used to design novel and subtype selective drugs.
History
DepositionApr 24, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 18, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
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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
E: Antibody scFv16
R: Green fluorescent protein,D(3) dopamine receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)190,1106
Polymers189,6765
Non-polymers4341
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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

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


Mass: 40097.500 Da / Num. of mol.: 1 / Mutation: S47N,G204A,E246A,M249K,A326S
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
#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
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: 7845.078 Da / Num. of mol.: 1 / Mutation: C68S
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

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Antibody / Protein / Non-polymers , 3 types, 3 molecules ER

#4: Antibody Antibody scFv16


Mass: 27625.844 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Trichoplusia ni (cabbage looper)
#5: Protein Green fluorescent protein,D(3) dopamine receptor / Dopamine D3 receptor


Mass: 74733.945 Da / Num. of mol.: 1 / Mutation: L119W
Source method: isolated from a genetically manipulated source
Details: HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP- ...Details: HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R
Source: (gene. exp.) Homo sapiens (human) / Gene: GFP, DRD3 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P42212, UniProt: P35462
#6: Chemical ChemComp-A1H9N / N-[2-[(1R,2S)-2-[[(2S,5S)-2-(6-azanylpyridin-3-yl)-5-methyl-morpholin-4-yl]methyl]cyclopropyl]ethyl]-1H-indole-2-carboxamide


Mass: 433.546 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H31N5O2 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY

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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: D3R: Gtrimer: scFv16 complex bound to the bitopic FOB02-04A - Conformation B
Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Molecular weightValue: 0.19 MDa / Experimental value: NO
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 mesh size: 300 divisions/in. / Grid type: Quantifoil R0.6/1
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN 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 / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K3 (6k x 4k) / Num. of real images: 22655
Image scansMovie frames/image: 50

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Processing

EM software
IDNameVersionCategory
1Topazparticle selection
2EPUimage acquisition
4RELION4CTF correction
9RELION4initial Euler assignment
11cryoSPARCclassification
12cryoSPARC3D reconstruction
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 19414230
3D reconstructionResolution: 3.09 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 159184 / Symmetry type: POINT
Atomic model buildingProtocol: OTHER / Space: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.018815
ELECTRON MICROSCOPYf_angle_d1.06911968
ELECTRON MICROSCOPYf_dihedral_angle_d12.0553146
ELECTRON MICROSCOPYf_chiral_restr0.0731379
ELECTRON MICROSCOPYf_plane_restr0.0051509

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