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- PDB-7jvq: Cryo-EM structure of apomorphine-bound dopamine receptor 1 in com... -

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Basic information

Entry
Database: PDB / ID: 7jvq
TitleCryo-EM structure of apomorphine-bound dopamine receptor 1 in complex with Gs protein
Components
  • (Guanine nucleotide-binding protein ...) x 2
  • D(1A) dopamine receptor
  • Engineered mini-Gi protein alpha sub-unit
  • Nanobody35
KeywordsSIGNALING PROTEIN / Dopamine receptor 1 / Gi protein / apomorphine
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsZhuang, Y. / Xu, P. / Mao, C. / Wang, L. / Krumm, B. / Zhou, X.E. / Huang, S. / Liu, H. / Cheng, X. / Huang, X.-P. ...Zhuang, Y. / Xu, P. / Mao, C. / Wang, L. / Krumm, B. / Zhou, X.E. / 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, B.L. / Zhang, Y. / Zhang, C. / Xu, H.E.
Funding support China, United States, 4items
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 Report
SummaryFull reportAbout validation report
History
DepositionAug 22, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 24, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 3, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

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Assembly

Deposited unit
R: D(1A) dopamine receptor
A: Engineered mini-Gi protein alpha sub-unit
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
N: Nanobody35
hetero molecules


Theoretical massNumber of molelcules
Total (without water)149,04314
Polymers146,0735
Non-polymers2,9709
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 3 types, 3 molecules RAN

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


Mass: 55668.707 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DRD1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P21728
#2: Protein Engineered mini-Gi protein alpha sub-unit


Mass: 29048.932 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)
#5: Protein Nanobody35


Mass: 14845.516 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli)

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

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


Mass: 39077.715 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: 7432.554 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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Non-polymers , 3 types, 9 molecules

#6: Chemical ChemComp-OR9 / (6aR)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol / Apomorphine


Mass: 267.322 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H17NO2 / Feature type: SUBJECT OF INVESTIGATION / Comment: antagonist*YM
#7: Chemical
ChemComp-CLR / CHOLESTEROL / Cholesterol


Mass: 386.654 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C27H46O
#8: Chemical ChemComp-PLM / PALMITIC ACID / Palmitic acid


Mass: 256.424 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C16H32O2

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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: SKF-81297-bound dopamine receptor 1 in complex with Gi protein
Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.2
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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 64 e/Å2 / Film or detector model: GATAN K2 BASE (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.13_2998: / Classification: refinement
CTF correctionType: NONE
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 650000 / Symmetry type: POINT

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