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- EMDB-35684: Dopamine Receptor D2R-Gi-Rotigotine complex -

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Entry
Database: EMDB / ID: EMD-35684
TitleDopamine Receptor D2R-Gi-Rotigotine complex
Map data
Sample
  • Complex: Dopamine Receptor D2R-Gi-Rotigotine complex
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: ScFv16
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Soluble cytochrome b562,D(2) dopamine receptor
  • Ligand: Rotigotine
KeywordsDopamine / Dopamine receptor / GPCR / D2R / Gi / Rotigotine / Polypharmacology Parkinson's disease / Restless legs syndrome / MEMBRANE PROTEIN
Function / homology
Function and homology information


negative regulation of dopamine receptor signaling pathway / positive regulation of dopamine uptake involved in synaptic transmission / nervous system process involved in regulation of systemic arterial blood pressure / negative regulation of dephosphorylation / positive regulation of glial cell-derived neurotrophic factor production / adenohypophysis development / acid secretion / regulation of synapse structural plasticity / dopamine neurotransmitter receptor activity, coupled via Gi/Go / response to histamine ...negative regulation of dopamine receptor signaling pathway / positive regulation of dopamine uptake involved in synaptic transmission / nervous system process involved in regulation of systemic arterial blood pressure / negative regulation of dephosphorylation / positive regulation of glial cell-derived neurotrophic factor production / adenohypophysis development / acid secretion / regulation of synapse structural plasticity / dopamine neurotransmitter receptor activity, coupled via Gi/Go / response to histamine / negative regulation of circadian sleep/wake cycle, sleep / regulation of locomotion involved in locomotory behavior / neuron-neuron synaptic transmission / regulation of potassium ion transport / negative regulation of cellular response to hypoxia / negative regulation of dopamine secretion / adenylate cyclase-inhibiting dopamine receptor signaling pathway / response to inactivity / cerebral cortex GABAergic interneuron migration / orbitofrontal cortex development / hyaloid vascular plexus regression / Dopamine receptors / branching morphogenesis of a nerve / peristalsis / regulation of dopamine uptake involved in synaptic transmission / dopamine binding / phospholipase C-activating dopamine receptor signaling pathway / positive regulation of growth hormone secretion / heterotrimeric G-protein binding / G protein-coupled receptor complex / beta-arrestin-dependent dopamine receptor signaling pathway / striatum development / drinking behavior / auditory behavior / positive regulation of G protein-coupled receptor signaling pathway / adult walking behavior / dopaminergic synapse / behavioral response to ethanol / non-motile cilium / G protein-coupled receptor internalization / positive regulation of neuroblast proliferation / response to iron ion / negative regulation of synaptic transmission, glutamatergic / arachidonate secretion / ciliary membrane / response to morphine / positive regulation of cytokinesis / regulation of synaptic transmission, GABAergic / negative regulation of cytosolic calcium ion concentration / regulation of sodium ion transport / dopamine metabolic process / temperature homeostasis / regulation of dopamine secretion / associative learning / response to axon injury / positive regulation of receptor internalization / lateral plasma membrane / negative regulation of protein secretion / response to light stimulus / negative regulation of insulin secretion / cellular response to ethanol / potassium channel regulator activity / endocytic vesicle / G-protein alpha-subunit binding / prepulse inhibition / sperm flagellum / postsynaptic modulation of chemical synaptic transmission / long-term memory / cellular response to retinoic acid / negative regulation of blood pressure / release of sequestered calcium ion into cytosol / axonogenesis / behavioral response to cocaine / regulation of eating behavior / adenylate cyclase inhibitor activity / T cell migration / presynaptic modulation of chemical synaptic transmission / positive regulation of protein localization to cell cortex / positive regulation of relaxation of smooth muscle / synapse assembly / Adenylate cyclase inhibitory pathway / regulation of heart rate / D2 dopamine receptor binding / negative regulation of innate immune response / response to amphetamine / ionotropic glutamate receptor binding / adenylate cyclase-inhibiting serotonin receptor signaling pathway / acrosomal vesicle / negative regulation of cell migration / G protein-coupled serotonin receptor binding / excitatory postsynaptic potential / axon terminus / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / cellular response to forskolin / locomotory behavior / regulation of mitotic spindle organization / positive regulation of long-term synaptic potentiation / mast cell degranulation / chemokine-mediated signaling pathway / response to nicotine
Similarity search - Function
Dopamine D2 receptor / Dopamine receptor family / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit ...Dopamine D2 receptor / Dopamine receptor family / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / 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. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / 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(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
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsXu P / Huang S / Zhuang Y / Mao C / Zhang Y / Wang Y / Li H / Jiang Y / Xu HE
Funding support China, 1 items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2018YFA0507002 China
CitationJournal: Cell Res / Year: 2023
Title: Structural genomics of the human dopamine receptor system.
Authors: Peiyu Xu / Sijie Huang / Brian E Krumm / Youwen Zhuang / Chunyou Mao / Yumu Zhang / Yue Wang / Xi-Ping Huang / Yong-Feng Liu / Xinheng He / Huadong Li / Wanchao Yin / Yi Jiang / Yan Zhang / ...Authors: Peiyu Xu / Sijie Huang / Brian E Krumm / Youwen Zhuang / Chunyou Mao / Yumu Zhang / Yue Wang / Xi-Ping Huang / Yong-Feng Liu / Xinheng He / Huadong Li / Wanchao Yin / Yi Jiang / Yan Zhang / Bryan L Roth / H Eric Xu /
Abstract: The dopaminergic system, including five dopamine receptors (D1R to D5R), plays essential roles in the central nervous system (CNS); and ligands that activate dopamine receptors have been used to ...The dopaminergic system, including five dopamine receptors (D1R to D5R), plays essential roles in the central nervous system (CNS); and ligands that activate dopamine receptors have been used to treat many neuropsychiatric disorders, including Parkinson's Disease (PD) and schizophrenia. Here, we report cryo-EM structures of all five subtypes of human dopamine receptors in complex with G protein and bound to the pan-agonist, rotigotine, which is used to treat PD and restless legs syndrome. The structures reveal the basis of rotigotine recognition in different dopamine receptors. Structural analysis together with functional assays illuminate determinants of ligand polypharmacology and selectivity. The structures also uncover the mechanisms of dopamine receptor activation, unique structural features among the five receptor subtypes, and the basis of G protein coupling specificity. Our work provides a comprehensive set of structural templates for the rational design of specific ligands to treat CNS diseases targeting the dopaminergic system.
History
DepositionMar 19, 2023-
Header (metadata) releaseJun 7, 2023-
Map releaseJun 7, 2023-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_35684.png

Downloads & links

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Map

FileDownload / File: emd_35684.map.gz / Format: CCP4 / Size: 27 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
1.05 Å/pix.
x 192 pix.
= 200.64 Å		1.05 Å/pix.
x 192 pix.
= 200.64 Å		1.05 Å/pix.
x 192 pix.
= 200.64 Å

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.045 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.04
Minimum - Maximum-0.28745267 - 0.37384346
Average (Standard dev.)-0.00016201661 (±0.009577773)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions192192192
Spacing192192192
CellA=B=C: 200.63998 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_35684_half_map_1.map
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Half map: #1

Fileemd_35684_half_map_2.map
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Sample components

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Entire : Dopamine Receptor D2R-Gi-Rotigotine complex

EntireName: Dopamine Receptor D2R-Gi-Rotigotine complex
Components
  • Complex: Dopamine Receptor D2R-Gi-Rotigotine complex
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: ScFv16
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Soluble cytochrome b562,D(2) dopamine receptor
  • Ligand: Rotigotine

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Supramolecule #1: Dopamine Receptor D2R-Gi-Rotigotine complex

SupramoleculeName: Dopamine Receptor D2R-Gi-Rotigotine complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Guanine nucleotide-binding protein G(i) subunit alpha-1

MacromoleculeName: Guanine nucleotide-binding protein G(i) subunit alpha-1
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.414047 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKNTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...String:
MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKNTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTTGIVETH FTFKDLHFKM FDVGAQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHASM KLFDSICNNK WFTDTSIILF LNKKDLFEEK IKKSPLTICY PEYAGSNTYE EAAAYIQCQF EDLNKRKDTK EIY THFTCS TDTKNVQFVF DAVTDVIIKN NLKDCGLF

UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1

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Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.915496 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MGSLLQSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG YLSCCRFLDD N QIVTSSGD ...String:
MGSLLQSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG YLSCCRFLDD N QIVTSSGD TTCALWDIET GQQTTTFTGH TGDVMSLSLA PDTRLFVSGA CDASAKLWDV REGMCRQTFT GHESDINAIC FF PNGNAFA TGSDDATCRL FDLRADQELM TYSHDNIICG ITSVSFSKSG RLLLAGYDDF NCNVWDALKA DRAGVLAGHD NRV SCLGVT DDGMAVATGS WDSFLKIWN

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #3: ScFv16

MacromoleculeName: ScFv16 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 26.466486 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS ...String:
DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS NGNTYLYWFL QRPGQSPQLL IYRMSNLASG VPDRFSGSGS GTAFTLTISR LEAEDVGVYY CMQHLEYPLT FG AGTKLEL K

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Macromolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Macromolecule #5: Soluble cytochrome b562,D(2) dopamine receptor

MacromoleculeName: Soluble cytochrome b562,D(2) dopamine receptor / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 67.234578 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: DYKDDDDAKL QTMHHHHHHH HHHHHHHHAD LEDNWETLND NLKVIEKADN AAQVKDALTK MRAAALDAQK ATPPKLEDKS PDSPEMKDF RHGFDILVGQ IDDALKLANE GKVKEAQAAA EQLKTTRNAY IQKYLASENL YFQGGTMDPL NLSWYDDDLE R QNWSRPFN ...String:
DYKDDDDAKL QTMHHHHHHH HHHHHHHHAD LEDNWETLND NLKVIEKADN AAQVKDALTK MRAAALDAQK ATPPKLEDKS PDSPEMKDF RHGFDILVGQ IDDALKLANE GKVKEAQAAA EQLKTTRNAY IQKYLASENL YFQGGTMDPL NLSWYDDDLE R QNWSRPFN GSDGKADRPH YNYYATLLTL LIAVIVFGNV LVCMAVSREK ALQTTTNYLI VSLAVADLLV ATLVMPWVVY LE VVGEWKF SRIHCDIFVT LDVMMCTASI LNLCAISIDR YTAVAMPMLY NTRYSSKRRV TVMISIVWVL SFTISCPLLF GLN NADQNE CIIANPAFVV YSSIVSFYVP FIVTLLVYIK IYIVLRRRRK RVNTKRSSRA FRAHLRAPLK GNCTHPEDMK LCTV IMKSN GSFPVNRRRV EAARRAQELE MEMLSSTSPP ERTRYSPIPP SHHQLTLPDP SHHGLHSTPD SPAKPEKNGH AKDHP KIAK IFEIQTMPNG KTRTSLKTMS RRKLSQQKEK KATQMLAIVL GVFIICWLPF FITHILNIHC DCNIPPVLYS AFTWLG YVN SAVNPIIYTT FNIEFRKAFL KILHC

UniProtKB: Soluble cytochrome b562, D(2) dopamine receptor

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Macromolecule #6: Rotigotine

MacromoleculeName: Rotigotine / type: ligand / ID: 6 / Number of copies: 1 / Formula: R5F
Molecular weightTheoretical: 315.473 Da
Chemical component information

ChemComp-R5F:
Rotigotine / medication, antidepressant, agonist*YM

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

22511

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 140237
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD

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