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- EMDB-22510: Cryo-EM structure of apomorphine-bound dopamine receptor 1 in com... -

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Basic information

Entry
Database: EMDB / ID: EMD-22510
TitleCryo-EM structure of apomorphine-bound dopamine receptor 1 in complex with Gs protein
Map data
SampleSKF-81297-bound dopamine receptor 1 in complex with Gi protein
  • D(1A) dopamine receptor
  • Engineered mini-Gi protein alpha sub-unit
  • (Guanine nucleotide-binding protein ...) x 2
  • Nanobody35
  • (ligand) x 3
Function / homology
Function and homology information


dopamine neurotransmitter receptor activity, coupled via Gs / dopamine neurotransmitter receptor activity / cerebral cortex GABAergic interneuron migration / habituation / dopamine binding / dopamine transport / regulation of dopamine uptake involved in synaptic transmission / histone H3-S10 phosphorylation / operant conditioning / phospholipase C-activating dopamine receptor signaling pathway ...dopamine neurotransmitter receptor activity, coupled via Gs / dopamine neurotransmitter receptor activity / cerebral cortex GABAergic interneuron migration / habituation / dopamine binding / dopamine transport / regulation of dopamine uptake involved in synaptic transmission / histone H3-S10 phosphorylation / operant conditioning / phospholipase C-activating dopamine receptor signaling pathway / sensitization / grooming behavior / glucose import / regulation of dopamine metabolic process / peristalsis / maternal behavior / dentate gyrus development / positive regulation of potassium ion transport / striatum development / positive regulation of cytosolic calcium ion concentration involved in phospholipase C-activating G protein-coupled signaling pathway / non-motile cilium / astrocyte development / conditioned taste aversion / dopamine receptor signaling pathway / temperature homeostasis / adult walking behavior / long-term synaptic depression / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / neuronal action potential / mating behavior / cardiac muscle cell apoptotic process / adenylate cyclase-activating adrenergic receptor signaling pathway / ciliary membrane / sensory perception of taste / G protein-coupled acetylcholine receptor signaling pathway / G-protein beta/gamma-subunit complex / G-protein gamma-subunit binding / cellular response to catecholamine stimulus / alkylglycerophosphoethanolamine phosphodiesterase activity / transmission of nerve impulse / rhodopsin mediated signaling pathway / adenylate cyclase-activating dopamine receptor signaling pathway / photoreceptor outer segment membrane / G-protein beta-subunit binding / dopamine metabolic process / photoreceptor disc membrane / GABA-ergic synapse / spectrin binding / cellular response to dopamine / heterotrimeric G-protein complex / behavioral response to cocaine / behavioral fear response / G protein-coupled receptor activity / activation of adenylate cyclase activity / synapse assembly / extracellular vesicle / Wnt signaling pathway, calcium modulating pathway / cellular response to prostaglandin E stimulus / positive regulation of synaptic transmission, glutamatergic / integral component of postsynaptic membrane / long-term synaptic potentiation / adenylate cyclase-activating G protein-coupled receptor signaling pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / prepulse inhibition / retina development in camera-type eye / GTPase binding / vasodilation / cilium / response to amphetamine / visual learning / photoreceptor inner segment / positive regulation of release of sequestered calcium ion into cytosol / regulation of protein phosphorylation / integral component of presynaptic membrane / memory / regulation of synaptic vesicle exocytosis / protein import into nucleus / cell population proliferation / cell body / lysosomal membrane / cellular response to hypoxia / positive regulation of cytosolic calcium ion concentration / Ras protein signal transduction / platelet activation / protein folding / dendritic spine / positive regulation of cell migration / GTPase activity / synapse / glutamatergic synapse / G protein-coupled receptor signaling pathway / response to drug / dendrite / endoplasmic reticulum membrane / protein-containing complex binding / positive regulation of gene expression / signal transduction / integral component of plasma membrane / extracellular exosome / membrane
G-protein, beta subunit / Dopamine D1 receptor / WD40-repeat-containing domain superfamily / G-protein gamma-like domain superfamily / G-protein beta WD-40 repeat / WD40 repeat, conserved site / WD40-repeat-containing domain / GPCR, rhodopsin-like, 7TM / Guanine nucleotide-binding protein, beta subunit / G protein-coupled receptor, rhodopsin-like ...G-protein, beta subunit / Dopamine D1 receptor / WD40-repeat-containing domain superfamily / G-protein gamma-like domain superfamily / G-protein beta WD-40 repeat / WD40 repeat, conserved site / WD40-repeat-containing domain / GPCR, rhodopsin-like, 7TM / Guanine nucleotide-binding protein, beta subunit / G protein-coupled receptor, rhodopsin-like / WD40/YVTN repeat-like-containing domain superfamily / G-protein gamma-like domain / G-protein, gamma subunit / WD40 repeat / Dopamine receptor family
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
Biological speciesHomo sapiens (human) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsZhuang Y / Xu P / Mao C / Wang L / Krumm B / Zhou XE / Huang S / Liu H / Cheng X / Huang X-P ...Zhuang Y / Xu P / Mao C / Wang L / Krumm B / Zhou XE / Huang S / Liu H / Cheng X / Huang X-P / Sheng D-D / Xu T / Liu Y-F / Wang Y / Guo J / Jiang Y / Jiang H / Melcher K / Roth BL / Zhang Y / Zhang C / Xu HE
Funding support China, United States, 4 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81922071 China
National Natural Science Foundation of China (NSFC)31770796 China
National Institutes of Health/National Institute of Mental Health (NIH/NIMH)RO1MH112205 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM128641 United States
CitationJournal: Cell / Year: 2021
Title: Structural insights into the human D1 and D2 dopamine receptor signaling complexes.
Authors: Youwen Zhuang / Peiyu Xu / Chunyou Mao / Lei Wang / Brian Krumm / X Edward Zhou / Sijie Huang / Heng Liu / Xi Cheng / Xi-Ping Huang / Dan-Dan Shen / Tinghai Xu / Yong-Feng Liu / Yue Wang / ...Authors: Youwen Zhuang / Peiyu Xu / Chunyou Mao / Lei Wang / Brian Krumm / X Edward Zhou / Sijie Huang / Heng Liu / Xi Cheng / Xi-Ping Huang / Dan-Dan Shen / Tinghai Xu / Yong-Feng Liu / Yue Wang / Jia Guo / Yi Jiang / Hualiang Jiang / Karsten Melcher / Bryan L Roth / Yan Zhang / Cheng Zhang / H Eric Xu /
Abstract: The D1- and D2-dopamine receptors (D1R and D2R), which signal through G and G, respectively, represent the principal stimulatory and inhibitory dopamine receptors in the central nervous system. D1R ...The D1- and D2-dopamine receptors (D1R and D2R), which signal through G and G, respectively, represent the principal stimulatory and inhibitory dopamine receptors in the central nervous system. D1R and D2R also represent the main therapeutic targets for Parkinson's disease, schizophrenia, and many other neuropsychiatric disorders, and insight into their signaling is essential for understanding both therapeutic and side effects of dopaminergic drugs. Here, we report four cryoelectron microscopy (cryo-EM) structures of D1R-G and D2R-G signaling complexes with selective and non-selective dopamine agonists, including two currently used anti-Parkinson's disease drugs, apomorphine and bromocriptine. These structures, together with mutagenesis studies, reveal the conserved binding mode of dopamine agonists, the unique pocket topology underlying ligand selectivity, the conformational changes in receptor activation, and potential structural determinants for G protein-coupling selectivity. These results provide both a molecular understanding of dopamine signaling and multiple structural templates for drug design targeting the dopaminergic system.
Validation ReportSummary, Full report, XML, About validation report
History
DepositionAug 22, 2020-
Header (metadata) releaseFeb 24, 2021-
Map releaseFeb 24, 2021-
UpdateMar 3, 2021-
Current statusMar 3, 2021Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.04
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by height
  • Surface level: 0.04
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7jvq
  • Surface level: 0.04
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_22510.png

Downloads & links

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Map

FileDownload / File: emd_22510.map.gz / Format: CCP4 / Size: 27 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.01 Å/pix.
x 192 pix.
= 194.688 Å		1.01 Å/pix.
x 192 pix.
= 194.688 Å		1.01 Å/pix.
x 192 pix.
= 194.688 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.014 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.02 / Movie #1: 0.04
Minimum - Maximum-0.34610474 - 0.49430704
Average (Standard dev.)-0.00020848481 (±0.012966496)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions192192192
Spacing192192192
CellA=B=C: 194.68802 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0141.0141.014
M x/y/z192192192
origin x/y/z0.0000.0000.000
length x/y/z194.688194.688194.688
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ410410410
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS192192192
D min/max/mean-0.3460.494-0.000

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Supplemental data

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Sample components

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Entire SKF-81297-bound dopamine receptor 1 in complex with Gi protein

EntireName: SKF-81297-bound dopamine receptor 1 in complex with Gi protein
Number of components: 9

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Component #1: protein, SKF-81297-bound dopamine receptor 1 in complex with Gi p...

ProteinName: SKF-81297-bound dopamine receptor 1 in complex with Gi protein
Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #2: protein, D(1A) dopamine receptor

ProteinName: D(1A) dopamine receptor / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 55.668707 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #3: protein, Engineered mini-Gi protein alpha sub-unit

ProteinName: Engineered mini-Gi protein alpha sub-unit / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 29.048932 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #4: protein, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subuni...

ProteinName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 39.077715 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #5: protein, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subuni...

ProteinName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 7.432554 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #6: protein, Nanobody35

ProteinName: Nanobody35 / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 14.845516 kDa
SourceSpecies: synthetic construct (others)
Source (engineered)Expression System: Escherichia coli (E. coli)

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Component #7: ligand, (6aR)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinol...

LigandName: (6aR)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 0.267322 kDa

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Component #8: ligand, CHOLESTEROL

LigandName: CHOLESTEROL / Number of Copies: 5 / Recombinant expression: No
MassTheoretical: 0.386654 kDa

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Component #9: ligand, PALMITIC ACID

LigandName: PALMITIC ACID / Number of Copies: 3 / Recombinant expression: No
MassTheoretical: 0.256424 kDa

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Experimental details

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Sample preparation

SpecimenSpecimen state: Particle / Method: cryo EM
Sample solutionpH: 7.2
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 64 e/Å2 / Illumination mode: FLOOD BEAM
LensImaging mode: BRIGHT FIELD
Specimen HolderModel: OTHER
CameraDetector: GATAN K2 BASE (4k x 4k)

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Image processing

ProcessingMethod: single particle reconstruction / Number of projections: 650000
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF

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Atomic model buiding

Output model

7jvq

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