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- EMDB-30410: Dopamine Receptor D3R-Gi-Pramipexole complex -

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Basic information

Entry
Database: EMDB / ID: EMD-30410
TitleDopamine Receptor D3R-Gi-Pramipexole complex
Map data
SampleDopamine Receptor D3R-Gi-Pramipexole complex
  • Guanine nucleotide-binding protein
  • (scfv16) x 2
  • chimera protein of Soluble cytochrome b562 and D(3) dopamine receptor
  • (Guanine nucleotide-binding protein ...) x 3
  • Soluble cytochrome b562,D(3) dopamine receptor
  • ligand
Function / homology
Function and homology information


musculoskeletal movement, spinal reflex action / acid secretion / regulation of locomotion involved in locomotory behavior / gastric emptying / dopamine neurotransmitter receptor activity, coupled via Gi/Go / regulation of potassium ion transport / response to histamine / negative regulation of sodium:proton antiporter activity / Dopamine receptors / positive regulation of dopamine receptor signaling pathway ...musculoskeletal movement, spinal reflex action / acid secretion / regulation of locomotion involved in locomotory behavior / gastric emptying / dopamine neurotransmitter receptor activity, coupled via Gi/Go / regulation of potassium ion transport / response to histamine / negative regulation of sodium:proton antiporter activity / Dopamine receptors / positive regulation of dopamine receptor signaling pathway / negative regulation of voltage-gated calcium channel activity / regulation of dopamine uptake involved in synaptic transmission / adenylate cyclase-inhibiting dopamine receptor signaling pathway / phospholipase C-activating dopamine receptor signaling pathway / negative regulation of oligodendrocyte differentiation / regulation of circadian sleep/wake cycle, sleep / negative regulation of adenylate cyclase activity / Adenylate cyclase inhibitory pathway / positive regulation of cytosolic calcium ion concentration involved in phospholipase C-activating G protein-coupled signaling pathway / positive regulation of renal sodium excretion / G protein-coupled receptor internalization / PLC beta mediated events / negative regulation of synaptic transmission, glutamatergic / regulation of postsynaptic neurotransmitter receptor internalization / positive regulation of protein localization to cell cortex / G protein-coupled serotonin receptor binding / cell cortex region / Olfactory Signaling Pathway / D1 dopamine receptor binding / Thromboxane signalling through TP receptor / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / regulation of dopamine secretion / Prostacyclin signalling through prostacyclin receptor / ADP signalling through P2Y purinoceptor 12 / G-protein activation / adenylate cyclase-activating adrenergic receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon signaling in metabolic regulation / cardiac muscle cell apoptotic process / regulation of mitotic spindle organization / regulation of cAMP-mediated signaling / G protein-coupled acetylcholine receptor signaling pathway / sensory perception of taste / G-protein beta/gamma-subunit complex / cellular response to forskolin / cellular response to catecholamine stimulus / G-protein gamma-subunit binding / G beta:gamma signalling through CDC42 / alkylglycerophosphoethanolamine phosphodiesterase activity / G alpha (z) signalling events / negative regulation of synaptic transmission / rhodopsin mediated signaling pathway / positive regulation of cytokinesis / Glucagon-type ligand receptors / G beta:gamma signalling through BTK / adenylate cyclase-activating dopamine receptor signaling pathway / Vasopressin regulates renal water homeostasis via Aquaporins / photoreceptor outer segment membrane / dopamine metabolic process / photoreceptor disc membrane / positive regulation of potassium ion transmembrane transport / G-protein beta-subunit binding / spectrin binding / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / behavioral response to cocaine / G-protein beta/gamma-subunit complex binding / arachidonic acid secretion / GTPase activating protein binding / negative regulation of cytosolic calcium ion concentration / heterotrimeric G-protein complex / GABA-ergic synapse / social behavior / response to morphine / G beta:gamma signalling through PI3Kgamma / negative regulation of protein kinase B signaling / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / G protein-coupled receptor activity / Regulation of insulin secretion / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / response to cocaine / endocytic vesicle / negative regulation of protein secretion / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / Wnt signaling pathway, calcium modulating pathway / cellular response to prostaglandin E stimulus / G alpha (12/13) signalling events / integral component of postsynaptic density membrane / ADORA2B mediated anti-inflammatory cytokines production / negative regulation of blood pressure / prepulse inhibition / phospholipase C-activating G protein-coupled receptor signaling pathway / cellular calcium ion homeostasis / response to peptide hormone
Similarity search - Function
Dopamine D3 receptor / Dopamine receptor family / G-protein alpha subunit, group I / Cytochrome b562 / Cytochrome b562 / G-protein gamma subunit domain profile. / G-protein, gamma subunit / Guanine nucleotide-binding protein, beta subunit / G-protein gamma-like domain superfamily / G-protein, beta subunit ...Dopamine D3 receptor / Dopamine receptor family / G-protein alpha subunit, group I / Cytochrome b562 / Cytochrome b562 / G-protein gamma subunit domain profile. / G-protein, gamma subunit / Guanine nucleotide-binding protein, beta subunit / G-protein gamma-like domain superfamily / G-protein, beta subunit / G protein gamma subunit-like motifs / G-protein gamma-like domain / GGL domain / Cytochrome c/b562 / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit / G-protein alpha subunit / G protein alpha subunit, helical insertion / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein coupled receptors family 1 signature. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Soluble cytochrome b562 / D(3) 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
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse) / Escherichia coli (E. coli)
Methodsingle particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsXu P / Huang S / Mao C / Krumm B / Zhou X / Tan Y / Huang X-P / Liu Y / Shen D-D / Jiang Y ...Xu P / Huang S / Mao C / Krumm B / Zhou X / Tan Y / Huang X-P / Liu Y / Shen D-D / Jiang Y / Yu X / Jiang H / Melcher K / Roth B / Cheng X / Zhang Y / Xu H
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)2018YFA0507002 China
CitationJournal: Mol Cell / Year: 2021
Title: Structures of the human dopamine D3 receptor-G complexes.
Authors: Peiyu Xu / Sijie Huang / Chunyou Mao / Brian E Krumm / X Edward Zhou / Yangxia Tan / Xi-Ping Huang / Yongfeng Liu / Dan-Dan Shen / Yi Jiang / Xuekui Yu / Hualiang Jiang / Karsten Melcher / ...Authors: Peiyu Xu / Sijie Huang / Chunyou Mao / Brian E Krumm / X Edward Zhou / Yangxia Tan / Xi-Ping Huang / Yongfeng Liu / Dan-Dan Shen / Yi Jiang / Xuekui Yu / Hualiang Jiang / Karsten Melcher / Bryan L Roth / Xi Cheng / Yan Zhang / H Eric Xu /
Abstract: The dopamine system, including five dopamine receptors (D1R-D5R), plays essential roles in the central nervous system (CNS), and ligands that activate dopamine receptors have been used to treat many ...The dopamine system, including five dopamine receptors (D1R-D5R), plays essential roles in the central nervous system (CNS), and ligands that activate dopamine receptors have been used to treat many neuropsychiatric disorders. Here, we report two cryo-EM structures of human D3R in complex with an inhibitory G protein and bound to the D3R-selective agonists PD128907 and pramipexole, the latter of which is used to treat patients with Parkinson's disease. The structures reveal agonist binding modes distinct from the antagonist-bound D3R structure and conformational signatures for ligand-induced receptor activation. Mutagenesis and homology modeling illuminate determinants of ligand specificity across dopamine receptors and the mechanisms for G protein coupling. Collectively our work reveals the basis of agonist binding and ligand-induced receptor activation and provides structural templates for designing specific ligands to treat CNS diseases targeting the dopaminergic system.
History
DepositionJul 29, 2020-
Header (metadata) releaseMar 10, 2021-
Map releaseMar 10, 2021-
UpdateApr 7, 2021-
Current statusApr 7, 2021Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.025
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.025
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7cmu
  • Surface level: 0.025
  • 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_30410.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
Contour LevelBy AUTHOR: 0.025 / Movie #1: 0.025
Minimum - Maximum-0.32101184 - 0.40604174
Average (Standard dev.)-0.000125434 (±0.01027981)
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/NZ300300300
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS192192192
D min/max/mean-0.3210.406-0.000

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Supplemental data

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Sample components

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Entire Dopamine Receptor D3R-Gi-Pramipexole complex

EntireName: Dopamine Receptor D3R-Gi-Pramipexole complex / Number of components: 10

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Component #1: protein, Dopamine Receptor D3R-Gi-Pramipexole complex

ProteinName: Dopamine Receptor D3R-Gi-Pramipexole complex / Recombinant expression: No

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Component #2: protein, Guanine nucleotide-binding protein

ProteinName: Guanine nucleotide-binding protein / Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #3: protein, scfv16

ProteinName: scfv16 / Recombinant expression: No
SourceSpecies: Mus musculus (house mouse)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #4: protein, chimera protein of Soluble cytochrome b562 and D(3) dopa...

ProteinName: chimera protein of Soluble cytochrome b562 and D(3) dopamine receptor
Recombinant expression: No
SourceSpecies: Escherichia coli (E. coli)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #5: 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 #6: 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: 37.915496 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #7: 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 #8: protein, scfv16

ProteinName: scfv16 / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 26.466486 kDa
SourceSpecies: Mus musculus (house mouse)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #9: protein, Soluble cytochrome b562,D(3) dopamine receptor

ProteinName: Soluble cytochrome b562,D(3) dopamine receptor
Details: chimera protein of Soluble cytochrome b562 and D(3) dopamine receptor
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 60.816801 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #10: ligand, (6S)-N6-propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-d...

LigandName: (6S)-N6-propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 0.211327 kDa

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Experimental details

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Sample preparation

SpecimenSpecimen state: Particle / Method: cryo EM
Sample solutionpH: 7.4
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 SUMMIT (4k x 4k)

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Image processing

ProcessingMethod: single particle reconstruction / Number of projections: 135278
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF

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Atomic model buiding

Output model

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