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- EMDB-22511: Cryo-EM structure of Bromocriptine-bound dopamine receptor 2 in c... -

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Basic information

Entry
Database: EMDB / ID: EMD-22511
TitleCryo-EM structure of Bromocriptine-bound dopamine receptor 2 in complex with Gi protein
Map data
SampleBromocriptin-bound dopamine receptor 2 in complex with Gi protein
  • Soluble cytochrome b562,D(2) dopamine receptor
  • (Guanine nucleotide-binding protein ...) x 3
  • Antibody fragment ScFv16
  • ligand
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 speciesHomo sapiens (human) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.8 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 31, 2021-
Current statusMar 31, 2021Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.07
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by height
  • Surface level: 0.07
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7jvr
  • Surface level: 0.07
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_22511.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.05 Å/pix.
x 200 pix.
= 209. Å
1.05 Å/pix.
x 200 pix.
= 209. Å
1.05 Å/pix.
x 200 pix.
= 209. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.045 Å
Density
Contour LevelBy AUTHOR: 0.02 / Movie #1: 0.07
Minimum - Maximum-0.018159717 - 1.7024584
Average (Standard dev.)0.0018967643 (±0.029162614)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 208.99998 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0451.0451.045
M x/y/z200200200
origin x/y/z0.0000.0000.000
length x/y/z209.000209.000209.000
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ410410410
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS200200200
D min/max/mean-0.0181.7020.002

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Supplemental data

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Sample components

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Entire Bromocriptin-bound dopamine receptor 2 in complex with Gi protein

EntireName: Bromocriptin-bound dopamine receptor 2 in complex with Gi protein
Number of components: 7

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Component #1: protein, Bromocriptin-bound dopamine receptor 2 in complex with G...

ProteinName: Bromocriptin-bound dopamine receptor 2 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, Soluble cytochrome b562,D(2) dopamine receptor

ProteinName: Soluble cytochrome b562,D(2) dopamine receptor / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 67.234578 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #3: protein, Guanine nucleotide-binding protein G(i) subunit alpha-1

ProteinName: Guanine nucleotide-binding protein G(i) subunit alpha-1
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 40.414047 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: 38.146707 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: 7.861143 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #6: protein, Antibody fragment ScFv16

ProteinName: Antibody fragment ScFv16 / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 28.813047 kDa
SourceSpecies: synthetic construct (others)
Source (engineered)Expression System: Escherichia coli (E. coli)

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Component #7: ligand, bromoergocryptine

LigandName: bromoergocryptine / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 0.654594 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: 632558
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF

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Atomic model buiding

Output model

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