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- PDB-7jvr: Cryo-EM structure of Bromocriptine-bound dopamine receptor 2 in c... -

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Basic information

Entry
Database: PDB / ID: 7jvr
TitleCryo-EM structure of Bromocriptine-bound dopamine receptor 2 in complex with Gi protein
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Antibody fragment ScFv16
  • Soluble cytochrome b562,D(2) dopamine receptor
KeywordsSIGNALING PROTEIN / Dopamine receptor 2 / Gi protein / bromocriptine
Function / homology
Function and homology information


positive regulation of dopamine uptake involved in synaptic transmission / acid secretion / regulation of locomotion involved in locomotory behavior / auditory behavior / negative regulation of circadian sleep/wake cycle, sleep / positive regulation of glial cell-derived neurotrophic factor production / negative regulation of dopamine receptor signaling pathway / dopamine neurotransmitter receptor activity, coupled via Gi/Go / nervous system process involved in regulation of systemic arterial blood pressure / regulation of synapse structural plasticity ...positive regulation of dopamine uptake involved in synaptic transmission / acid secretion / regulation of locomotion involved in locomotory behavior / auditory behavior / negative regulation of circadian sleep/wake cycle, sleep / positive regulation of glial cell-derived neurotrophic factor production / negative regulation of dopamine receptor signaling pathway / dopamine neurotransmitter receptor activity, coupled via Gi/Go / nervous system process involved in regulation of systemic arterial blood pressure / regulation of synapse structural plasticity / regulation of potassium ion transport / response to histamine / adenohypophysis development / hyaloid vascular plexus regression / cerebral cortex GABAergic interneuron migration / negative regulation of dopamine secretion / neuron-neuron synaptic transmission / dopamine binding / dopaminergic synapse / negative regulation of voltage-gated calcium channel activity / response to inactivity / regulation of dopamine uptake involved in synaptic transmission / positive regulation of growth hormone secretion / adenylate cyclase-inhibiting dopamine receptor signaling pathway / regulation of phosphoprotein phosphatase activity / orbitofrontal cortex development / postsynaptic modulation of chemical synaptic transmission / branching morphogenesis of a nerve / phospholipase C-activating dopamine receptor signaling pathway / grooming behavior / negative regulation of innate immune response / peristalsis / behavioral response to ethanol / negative regulation of adenylate cyclase activity / positive regulation of urine volume / synaptic transmission, dopaminergic / striatum development / G protein-coupled receptor internalization / positive regulation of cytosolic calcium ion concentration involved in phospholipase C-activating G protein-coupled signaling pathway / drinking behavior / pigmentation / non-motile cilium / G protein-coupled serotonin receptor binding / positive regulation of protein localization to cell cortex / negative regulation of synaptic transmission, glutamatergic / response to iron ion / positive regulation of renal sodium excretion / positive regulation of multicellular organism growth / temperature homeostasis / cell cortex region / adult walking behavior / regulation of dopamine secretion / 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 / potassium channel regulator activity / regulation of mitotic spindle organization / regulation of synaptic transmission, GABAergic / regulation of cAMP-mediated signaling / G-protein beta/gamma-subunit complex / cellular response to catecholamine stimulus / G-protein gamma-subunit binding / alkylglycerophosphoethanolamine phosphodiesterase activity / sensory perception of smell / positive regulation of cytokinesis / negative regulation of synaptic transmission / cellular response to forskolin / positive regulation of G protein-coupled receptor signaling pathway / rhodopsin mediated signaling pathway / adenylate cyclase-activating dopamine receptor signaling pathway / photoreceptor outer segment membrane / G-protein beta-subunit binding / positive regulation of neuroblast proliferation / dopamine metabolic process / photoreceptor disc membrane / GABA-ergic synapse / spectrin binding / G-protein beta/gamma-subunit complex binding / GTPase activating protein binding / arachidonic acid secretion / sperm flagellum / ionotropic glutamate receptor binding / negative regulation of cytosolic calcium ion concentration / positive regulation of receptor internalization / heterotrimeric G-protein complex / response to morphine / behavioral response to cocaine / lateral plasma membrane / response to light stimulus / release of sequestered calcium ion into cytosol / axon terminus / negative regulation of protein kinase B signaling / negative regulation of insulin secretion / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / response to cocaine / excitatory postsynaptic potential / long-term memory / associative learning
P-loop containing nucleoside triphosphate hydrolase / G-protein, gamma subunit / G-protein gamma-like domain superfamily / WD40-repeat-containing domain superfamily / G-protein, beta subunit / G-protein beta WD-40 repeat / WD40 repeat / G protein alpha subunit, helical insertion / Dopamine receptor family / WD40 repeat, conserved site ...P-loop containing nucleoside triphosphate hydrolase / G-protein, gamma subunit / G-protein gamma-like domain superfamily / WD40-repeat-containing domain superfamily / G-protein, beta subunit / G-protein beta WD-40 repeat / WD40 repeat / G protein alpha subunit, helical insertion / Dopamine receptor family / WD40 repeat, conserved site / G protein-coupled receptor, rhodopsin-like / WD40-repeat-containing domain / G-protein gamma-like domain / Cytochrome c/b562 / Cytochrome b562 / G-protein alpha subunit, group I / WD40/YVTN repeat-like-containing domain superfamily / Guanine nucleotide binding protein (G-protein), alpha subunit / Dopamine D2 receptor / GPCR, rhodopsin-like, 7TM / Guanine nucleotide-binding protein, beta subunit
Soluble cytochrome b562 / D(2) 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(i) subunit alpha-1
Biological speciesEscherichia coli (E. coli)
Homo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 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
Revision 2.0Mar 31, 2021Group: Atomic model / Data collection / Structure summary / Category: atom_site / em_software / entity
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _em_software.category / _em_software.fitting_id / _em_software.imaging_id / _entity.pdbx_description
Description: Ligand geometry
Details: Corrected the configurations of two nitrogen atoms in the ligand bromoergocryptine.
Provider: author / Type: Coordinate replacement

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Structure visualization

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Assembly

Deposited unit
R: Soluble cytochrome b562,D(2) dopamine receptor
A: Guanine nucleotide-binding protein G(i) subunit alpha-1
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 fragment ScFv16
hetero molecules


Theoretical massNumber of molelcules
Total (without water)183,1246
Polymers182,4705
Non-polymers6551
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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

#2: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40414.047 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63096
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 38146.707 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: 7861.143 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 / Non-polymers , 3 types, 3 molecules RE

#1: Protein Soluble cytochrome b562,D(2) dopamine receptor / Cytochrome b-562 / Dopamine D2 receptor


Mass: 67234.578 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli (E. coli), (gene. exp.) Homo sapiens (human)
Gene: cybC, DRD2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P0ABE7, UniProt: P14416
#5: Antibody Antibody fragment ScFv16


Mass: 28813.047 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)
#6: Chemical ChemComp-08Y / bromoergocryptine / bromocriptine / Bromocriptine


Mass: 654.594 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H40BrN5O5 / Feature type: SUBJECT OF INVESTIGATION / Comment: agonist*YM

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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: Bromocriptin-bound dopamine receptor 2 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: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 632558 / Symmetry type: POINT

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