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- PDB-7x2c: Cryo-EM structure of the fenoldopam-bound D1 dopamine receptor an... -

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Basic information

Entry
Database: PDB / ID: 7x2c
TitleCryo-EM structure of the fenoldopam-bound D1 dopamine receptor and mini-Gs complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • D(1A) dopamine receptor
  • Nanobody35
KeywordsSIGNALING PROTEIN / GPCR / dopamine receptor / mini-Gs / membrane protein
Function / homology
Function and homology information


dopamine neurotransmitter receptor activity, coupled via Gs / cerebral cortex GABAergic interneuron migration / dopamine neurotransmitter receptor activity / Dopamine receptors / dopamine binding / regulation of dopamine uptake involved in synaptic transmission / phospholipase C-activating dopamine receptor signaling pathway / heterotrimeric G-protein binding / 9+0 non-motile cilium / modification of postsynaptic structure ...dopamine neurotransmitter receptor activity, coupled via Gs / cerebral cortex GABAergic interneuron migration / dopamine neurotransmitter receptor activity / Dopamine receptors / dopamine binding / regulation of dopamine uptake involved in synaptic transmission / phospholipase C-activating dopamine receptor signaling pathway / heterotrimeric G-protein binding / 9+0 non-motile cilium / modification of postsynaptic structure / adult walking behavior / positive regulation of potassium ion transport / G protein-coupled receptor complex / arrestin family protein binding / non-motile cilium / G protein-coupled dopamine receptor signaling pathway / mating behavior / ciliary membrane / dopamine metabolic process / transmission of nerve impulse / G-protein alpha-subunit binding / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / adenylate cyclase-activating adrenergic receptor signaling pathway / positive regulation of synaptic transmission, glutamatergic / synapse assembly / visual learning / presynaptic modulation of chemical synaptic transmission / positive regulation of release of sequestered calcium ion into cytosol / vasodilation / GABA-ergic synapse / G protein-coupled receptor activity / 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 / cilium / 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 / G alpha (12/13) signalling events / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / extracellular vesicle / Thrombin signalling through proteinase activated receptors (PARs) / adenylate cyclase-activating G protein-coupled receptor signaling pathway / signaling receptor complex adaptor activity / GTPase binding / 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 / dendritic spine / G alpha (s) signalling events / G alpha (q) signalling events / positive regulation of MAPK cascade / Ras protein signal transduction / Extra-nuclear estrogen signaling / postsynaptic membrane / response to xenobiotic stimulus / positive regulation of cell migration / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / endoplasmic reticulum membrane / synapse / protein-containing complex binding / glutamatergic synapse / signal transduction / extracellular exosome / membrane / nucleus / plasma membrane / cytosol
Similarity search - Function
Dopamine D1 receptor / Dopamine receptor family / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily ...Dopamine D1 receptor / Dopamine receptor family / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / Serpentine type 7TM GPCR chemoreceptor Srsx / 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. / P-loop containing nucleotide triphosphate hydrolases / 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 / Rossmann fold / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
CHOLESTEROL / Chem-G3C / 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
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsTeng, X. / Zheng, S.
Funding support China, 1items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China) China
CitationJournal: Nat Commun / Year: 2022
Title: Ligand recognition and biased agonism of the D1 dopamine receptor.
Authors: Xiao Teng / Sijia Chen / Yingying Nie / Peng Xiao / Xiao Yu / Zhenhua Shao / Sanduo Zheng /
Abstract: Dopamine receptors are widely distributed in the central nervous system and are important therapeutic targets for treatment of various psychiatric and neurological diseases. Here, we report three ...Dopamine receptors are widely distributed in the central nervous system and are important therapeutic targets for treatment of various psychiatric and neurological diseases. Here, we report three cryo-electron microscopy structures of the D1 dopamine receptor (D1R)-Gs complex bound to two agonists, fenoldopam and tavapadon, and a positive allosteric modulator LY3154207. The structure reveals unusual binding of two fenoldopam molecules, one to the orthosteric binding pocket (OBP) and the other to the extended binding pocket (EBP). In contrast, one elongated tavapadon molecule binds to D1R, extending from OBP to EBP. Moreover, LY3154207 stabilizes the second intracellular loop of D1R in an alpha helical conformation to efficiently engage the G protein. Through a combination of biochemical, biophysical and cellular assays, we further show that the broad conformation stabilized by two fenoldopam molecules and interaction between TM5 and the agonist are important for biased signaling of D1R.
History
DepositionFeb 25, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 29, 2022Provider: repository / Type: Initial release
Revision 1.0Jun 29, 2022Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jun 29, 2022Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jun 29, 2022Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Jun 29, 2022Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jun 29, 2022Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Nov 13, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.2Jul 2, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1Jul 2, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
F: D(1A) dopamine receptor
A: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
D: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
E: Nanobody35
hetero molecules


Theoretical massNumber of molelcules
Total (without water)146,9318
Polymers145,9335
Non-polymers9983
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 2 types, 2 molecules FE

#1: Protein D(1A) dopamine receptor / Dopamine D1 receptor


Mass: 52409.656 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DRD1 / Production host: Homo sapiens (human) / References: UniProt: P21728
#5: Protein Nanobody35


Mass: 17352.498 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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

#2: Protein Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short


Mass: 28907.684 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAS / Production host: Homo sapiens (human)
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 39418.086 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P62873
#4: 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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Non-polymers , 2 types, 3 molecules

#6: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H46O
#7: Chemical ChemComp-G3C / (1R)-6-chloranyl-1-(4-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol


Mass: 305.756 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H16ClNO3 / 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

Component
IDNameTypeEntity IDParent-IDSource
1Cryo-EM structure of the fenoldopam-bound D1R-miniGs complexCOMPLEX#1-#50MULTIPLE SOURCES
2the fenoldopam-bound D1R-miniGsCOMPLEX#1-#21RECOMBINANT
3nanobody35COMPLEX#51RECOMBINANT
4Gbeta-1gama-2COMPLEX#3-#42RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
34Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
34Spodoptera frugiperda (fall armyworm)7108
Buffer solutionpH: 7.5
SpecimenConc.: 4 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 R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 281 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 magnification: 64000 X / Nominal defocus max: 2100 nm / Nominal defocus min: 800 nm
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of real images: 1035

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Processing

SoftwareName: PHENIX / Version: 1.19_4092: / Classification: refinement
EM software
IDNameVersionCategoryDetails (eV)
4cryoSPARCv3CTF correctionCTF parameters were estimated using patch-based CTF estimation
8PHENIXmodel refinement
12cryoSPARCclassification
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1791079
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 124932 / Num. of class averages: 1 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0038130
ELECTRON MICROSCOPYf_angle_d0.54311080
ELECTRON MICROSCOPYf_dihedral_angle_d4.611115
ELECTRON MICROSCOPYf_chiral_restr0.0421278
ELECTRON MICROSCOPYf_plane_restr0.0051403

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