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- PDB-8irs: Dopamine Receptor D2R-Gi-Rotigotine complex -

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Basic information

Entry
Database: PDB / ID: 8irs
TitleDopamine Receptor D2R-Gi-Rotigotine complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • ScFv16
  • Soluble cytochrome b562,D(2) dopamine receptor
KeywordsMEMBRANE PROTEIN / Dopamine / Dopamine receptor / GPCR / D2R / Gi / Rotigotine / Polypharmacology Parkinson's disease / Restless legs syndrome
Function / homology
Function and homology information


negative regulation of dopamine receptor signaling pathway / positive regulation of dopamine uptake involved in synaptic transmission / negative regulation of dephosphorylation / positive regulation of glial cell-derived neurotrophic factor production / acid secretion / dopamine neurotransmitter receptor activity, coupled via Gi/Go / nervous system process involved in regulation of systemic arterial blood pressure / response to histamine / negative regulation of circadian sleep/wake cycle, sleep / regulation of synapse structural plasticity ...negative regulation of dopamine receptor signaling pathway / positive regulation of dopamine uptake involved in synaptic transmission / negative regulation of dephosphorylation / positive regulation of glial cell-derived neurotrophic factor production / acid secretion / dopamine neurotransmitter receptor activity, coupled via Gi/Go / nervous system process involved in regulation of systemic arterial blood pressure / response to histamine / negative regulation of circadian sleep/wake cycle, sleep / regulation of synapse structural plasticity / regulation of locomotion involved in locomotory behavior / neuron-neuron synaptic transmission / negative regulation of cellular response to hypoxia / adenylate cyclase-inhibiting dopamine receptor signaling pathway / adenohypophysis development / response to inactivity / orbitofrontal cortex development / regulation of potassium ion transport / hyaloid vascular plexus regression / negative regulation of neuron migration / negative regulation of dopamine secretion / cerebral cortex GABAergic interneuron migration / Dopamine receptors / branching morphogenesis of a nerve / regulation of dopamine uptake involved in synaptic transmission / dopamine binding / positive regulation of growth hormone secretion / heterotrimeric G-protein binding / phospholipase C-activating dopamine receptor signaling pathway / peristalsis / beta-arrestin-dependent dopamine receptor signaling pathway / G protein-coupled receptor complex / grooming behavior / drinking behavior / positive regulation of renal sodium excretion / auditory behavior / striatum development / positive regulation of G protein-coupled receptor signaling pathway / dopaminergic synapse / behavioral response to ethanol / positive regulation of multicellular organism growth / G protein-coupled receptor internalization / non-motile cilium / response to iron ion / positive regulation of urine volume / negative regulation of synaptic transmission, glutamatergic / adult walking behavior / arachidonate secretion / ciliary membrane / positive regulation of neuroblast proliferation / response to morphine / regulation of synaptic transmission, GABAergic / positive regulation of cytokinesis / negative regulation of cytosolic calcium ion concentration / temperature homeostasis / pigmentation / dopamine uptake involved in synaptic transmission / dopamine metabolic process / regulation of dopamine secretion / positive regulation of receptor internalization / neuroblast proliferation / lateral plasma membrane / cellular response to ethanol / associative learning / negative regulation of protein secretion / response to light stimulus / G-protein alpha-subunit binding / endocytic vesicle / potassium channel regulator activity / prepulse inhibition / sperm flagellum / response to axon injury / long-term memory / postsynaptic modulation of chemical synaptic transmission / regulation of sodium ion transport / cellular response to retinoic acid / adenylate cyclase inhibitor activity / positive regulation of protein localization to cell cortex / negative regulation of blood pressure / T cell migration / positive regulation of relaxation of smooth muscle / behavioral response to cocaine / Adenylate cyclase inhibitory pathway / release of sequestered calcium ion into cytosol / D2 dopamine receptor binding / synapse assembly / adenylate cyclase-inhibiting serotonin receptor signaling pathway / G protein-coupled serotonin receptor binding / axonogenesis / ionotropic glutamate receptor binding / regulation of heart rate / epithelial cell proliferation / cellular response to forskolin / negative regulation of innate immune response / presynaptic modulation of chemical synaptic transmission / axon terminus / acrosomal vesicle / negative regulation of cell migration / regulation of mitotic spindle organization / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
Similarity search - Function
Dopamine D2 receptor / Dopamine receptor family / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / YVTN repeat-like/Quinoprotein amine dehydrogenase / G-protein alpha subunit, group I / 7 Propeller / Methylamine Dehydrogenase; Chain H / Serpentine type 7TM GPCR chemoreceptor Srsx ...Dopamine D2 receptor / Dopamine receptor family / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / YVTN repeat-like/Quinoprotein amine dehydrogenase / G-protein alpha subunit, group I / 7 Propeller / Methylamine Dehydrogenase; Chain H / Serpentine type 7TM GPCR chemoreceptor Srsx / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / 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 / Immunoglobulins / Immunoglobulin-like / Sandwich / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta
Similarity search - Domain/homology
Rotigotine / 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)
Escherichia coli (E. coli)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsXu, P. / Huang, S. / Zhuang, Y. / Mao, C. / Zhang, Y. / Wang, Y. / Li, H. / Jiang, Y. / Zhang, Y. / Xu, H.E.
Funding support China, 1items
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, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 7, 2023Provider: repository / Type: Initial release
Revision 1.1Aug 16, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Nov 8, 2023Group: Derived calculations / Structure summary / Category: chem_comp / entity / pdbx_entity_nonpoly
Item: _chem_comp.name / _chem_comp.pdbx_synonyms ..._chem_comp.name / _chem_comp.pdbx_synonyms / _entity.pdbx_description / _pdbx_entity_nonpoly.name
Revision 1.3Nov 6, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(i) subunit alpha-1
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
E: ScFv16
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
R: Soluble cytochrome b562,D(2) dopamine receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)180,2076
Polymers179,8925
Non-polymers3151
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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

#1: 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: Trichoplusia ni (cabbage looper) / References: UniProt: P63096
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37915.496 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Trichoplusia ni (cabbage looper) / 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: Trichoplusia ni (cabbage looper) / References: UniProt: P59768

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Antibody / Protein / Non-polymers , 3 types, 3 molecules ER

#3: Antibody ScFv16


Mass: 26466.486 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Trichoplusia ni (cabbage looper)
#5: 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: Trichoplusia ni (cabbage looper) / References: UniProt: P0ABE7, UniProt: P14416
#6: Chemical ChemComp-R5F / Rotigotine / (6~{S})-6-[propyl(2-thiophen-2-ylethyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol


Mass: 315.473 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H25NOS / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, antidepressant, agonist*YM

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Details

Has ligand of interestY
Has protein modificationY

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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: Dopamine Receptor D2R-Gi-Rotigotine complex / Type: COMPLEX / Entity ID: #1-#5 / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE-PROPANE

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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 FIELD / Nominal defocus max: 3000 nm / Nominal defocus min: 1200 nm / Cs: 2.7 mm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 140237 / Symmetry type: POINT

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