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- PDB-7jvp: Cryo-EM structure of SKF-83959-bound dopamine receptor 1 in compl... -

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Entry
Database: PDB / ID: 7jvp
TitleCryo-EM structure of SKF-83959-bound dopamine receptor 1 in complex with Gs protein
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • D(1A) dopamine receptor
  • nanobody 35Single-domain antibody
KeywordsSIGNALING PROTEIN / Dopamine receptor 1 / Gi protein / SKF-83959
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 / hair follicle placode formation / intrinsic component of membrane / conditioned taste aversion / intracellular transport / 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 / developmental growth / alkylglycerophosphoethanolamine phosphodiesterase activity / transmission of nerve impulse / sensory perception of smell / positive regulation of cAMP-mediated signaling / 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 / G-protein beta/gamma-subunit complex binding / bone development / cellular response to glucagon stimulus / renal water homeostasis / heterotrimeric G-protein complex / behavioral response to cocaine / behavioral fear response / adenylate cyclase activator activity / trans-Golgi network membrane / 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 / regulation of insulin secretion / cilium / response to amphetamine / visual learning / photoreceptor inner segment / cognition / 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 / platelet aggregation / protein import into nucleus / positive regulation of cold-induced thermogenesis / positive regulation of GTPase activity / cell population proliferation / cell body / lysosomal membrane / cellular response to hypoxia / positive regulation of cytosolic calcium ion concentration / Ras protein signal transduction
Dopamine D1 receptor / G protein-coupled receptor, rhodopsin-like / G-protein alpha subunit, group S / G-protein, beta subunit / WD40 repeat / G-protein, gamma subunit / G protein alpha subunit, helical insertion / G-protein gamma-like domain / WD40/YVTN repeat-like-containing domain superfamily / Guanine nucleotide-binding protein, beta subunit ...Dopamine D1 receptor / G protein-coupled receptor, rhodopsin-like / G-protein alpha subunit, group S / G-protein, beta subunit / WD40 repeat / G-protein, gamma subunit / G protein alpha subunit, helical insertion / G-protein gamma-like domain / WD40/YVTN repeat-like-containing domain superfamily / Guanine nucleotide-binding protein, beta subunit / Dopamine receptor family / GPCR, rhodopsin-like, 7TM / WD40-repeat-containing domain / WD40 repeat, conserved site / G-protein beta WD-40 repeat / P-loop containing nucleoside triphosphate hydrolase / G-protein gamma-like domain superfamily / WD40-repeat-containing domain superfamily / Guanine nucleotide binding protein (G-protein), alpha subunit
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 / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 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: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
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: nanobody 35
hetero molecules


Theoretical massNumber of molelcules
Total (without water)166,56917
Polymers162,6495
Non-polymers3,92012
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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

#2: Protein Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Adenylate cyclase-stimulating G alpha protein


Mass: 45624.352 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAS, GNAS1, GSP / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63092
#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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Protein / Antibody , 2 types, 2 molecules RN

#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
#5: Antibody nanobody 35 / Single-domain antibody


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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Non-polymers , 3 types, 12 molecules

#6: Chemical ChemComp-SK9 / (1R)-6-chloro-3-methyl-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol


Mass: 317.810 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H20ClNO2 / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical
ChemComp-CLR / CHOLESTEROL / Cholesterol


Mass: 386.654 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C27H46O
#8: Chemical
ChemComp-PLM / PALMITIC ACID / Palmitic acid


Mass: 256.424 Da / Num. of mol.: 5 / 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: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 679728 / Symmetry type: POINT

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