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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


regulation of locomotion involved in locomotory behavior / negative regulation of dopamine receptor signaling pathway / positive regulation of dopamine uptake involved in synaptic transmission / negative regulation of circadian sleep/wake cycle, sleep / acid secretion / positive regulation of glial cell-derived neurotrophic factor production / dopamine neurotransmitter receptor activity, coupled via Gi/Go / auditory behavior / nervous system process involved in regulation of systemic arterial blood pressure / regulation of synapse structural plasticity ...regulation of locomotion involved in locomotory behavior / negative regulation of dopamine receptor signaling pathway / positive regulation of dopamine uptake involved in synaptic transmission / negative regulation of circadian sleep/wake cycle, sleep / acid secretion / positive regulation of glial cell-derived neurotrophic factor production / dopamine neurotransmitter receptor activity, coupled via Gi/Go / auditory behavior / nervous system process involved in regulation of systemic arterial blood pressure / regulation of synapse structural plasticity / response to histamine / positive regulation of renal sodium excretion / adenohypophysis development / neuron-neuron synaptic transmission / hyaloid vascular plexus regression / cerebral cortex GABAergic interneuron migration / regulation of potassium ion transport / negative regulation of neuron migration / Dopamine receptors / adenylate cyclase-inhibiting dopamine receptor signaling pathway / negative regulation of cellular response to hypoxia / orbitofrontal cortex development / response to inactivity / dopamine binding / regulation of dopamine uptake involved in synaptic transmission / branching morphogenesis of a nerve / negative regulation of voltage-gated calcium channel activity / negative regulation of dopamine secretion / positive regulation of growth hormone secretion / heterotrimeric G-protein binding / behavioral response to ethanol / dopaminergic synapse / drinking behavior / peristalsis / G protein-coupled receptor complex / phospholipase C-activating dopamine receptor signaling pathway / grooming behavior / positive regulation of G protein-coupled receptor signaling pathway / positive regulation of urine volume / striatum development / negative regulation of adenylate cyclase activity / positive regulation of multicellular organism growth / negative regulation of synaptic transmission, glutamatergic / G protein-coupled receptor internalization / non-motile cilium / response to morphine / adult walking behavior / response to iron ion / ciliary membrane / dopamine uptake involved in synaptic transmission / regulation of synaptic transmission, GABAergic / arachidonic acid secretion / temperature homeostasis / pigmentation / postsynaptic modulation of chemical synaptic transmission / dopamine metabolic process / heterocyclic compound binding / positive regulation of neuroblast proliferation / negative regulation of cytosolic calcium ion concentration / regulation of dopamine secretion / positive regulation of cytokinesis / associative learning / positive regulation of receptor internalization / behavioral response to cocaine / lateral plasma membrane / endocytic vesicle / G-protein alpha-subunit binding / neuroblast proliferation / response to axon injury / sperm flagellum / response to light stimulus / GABA-ergic synapse / potassium channel regulator activity / Adenylate cyclase inhibitory pathway / negative regulation of protein secretion / positive regulation of protein localization to cell cortex / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / regulation of cAMP-mediated signaling / negative regulation of insulin secretion / D2 dopamine receptor binding / prepulse inhibition / long-term memory / G protein-coupled serotonin receptor binding / axon terminus / adenylate cyclase-activating adrenergic receptor signaling pathway / regulation of sodium ion transport / release of sequestered calcium ion into cytosol / regulation of mitotic spindle organization / cellular response to forskolin / synapse assembly / response to amphetamine / presynaptic modulation of chemical synaptic transmission / negative regulation of blood pressure / negative regulation of innate immune response / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / excitatory postsynaptic potential / regulation of heart rate / negative regulation of cell migration / axonogenesis / phosphatidylinositol 3-kinase/protein kinase B signal transduction
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-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion ...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-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / 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. / WD domain, G-beta repeat / 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 8, 2023-
Current statusNov 8, 2023Processing 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)
Voxel sizeX=Y=Z: 1.045 Å
Density
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
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_35684_half_map_2.map
Projections & Slices
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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

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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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