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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


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 / regulation of defecation / negative regulation of dopamine receptor signaling pathway / negative regulation of circadian sleep/wake cycle, sleep / regulation of locomotion involved in locomotory behavior / acid secretion ...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 / regulation of defecation / negative regulation of dopamine receptor signaling pathway / negative regulation of circadian sleep/wake cycle, sleep / regulation of locomotion involved in locomotory behavior / acid secretion / dopamine neurotransmitter receptor activity, coupled via Gi/Go / neuron-neuron synaptic transmission / response to histamine / peristalsis / positive regulation of behavioral fear response / regulation of synaptic transmission, GABAergic / regulation of potassium ion transport / negative regulation of cellular response to hypoxia / response to inactivity / orbitofrontal cortex development / cerebral cortex GABAergic interneuron migration / dopamine neurotransmitter receptor activity / negative regulation of dopamine secretion / hyaloid vascular plexus regression / branching morphogenesis of a nerve / Dopamine receptors / drinking behavior / dopamine binding / regulation of dopamine uptake involved in synaptic transmission / regulation of synapse structural plasticity / positive regulation of growth hormone secretion / phospholipase C-activating dopamine receptor signaling pathway / striatum development / heterotrimeric G-protein binding / beta-arrestin-dependent dopamine receptor signaling pathway / auditory behavior / adult walking behavior / positive regulation of G protein-coupled receptor signaling pathway / G protein-coupled receptor complex / 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 / cellular response to ethanol / arachidonate secretion / ciliary membrane / response to morphine / dopamine metabolic process / positive regulation of cytokinesis / temperature homeostasis / regulation of sodium ion transport / negative regulation of cytosolic calcium ion concentration / response to axon injury / associative learning / response to light stimulus / potassium channel regulator activity / positive regulation of receptor internalization / regulation of dopamine secretion / negative regulation of insulin secretion / negative regulation of protein secretion / lateral plasma membrane / endocytic vesicle / G-protein alpha-subunit binding / prepulse inhibition / postsynaptic modulation of chemical synaptic transmission / long-term memory / cellular response to retinoic acid / sperm flagellum / regulation of long-term neuronal synaptic plasticity / negative regulation of blood pressure / release of sequestered calcium ion into cytosol / axonogenesis / behavioral response to cocaine / regulation of heart rate / response to amphetamine / Wnt signaling pathway / regulation of eating behavior / adenylate cyclase inhibitor activity / T cell migration / positive regulation of protein localization to cell cortex / synapse assembly / positive regulation of relaxation of smooth muscle / Adenylate cyclase inhibitory pathway / visual learning / D2 dopamine receptor binding / presynaptic modulation of chemical synaptic transmission / negative regulation of innate immune response / adenylate cyclase-inhibiting dopamine receptor signaling pathway / negative regulation of cell migration / ionotropic glutamate receptor binding / adenylate cyclase-inhibiting serotonin receptor signaling pathway / G protein-coupled serotonin receptor binding / regulation of G protein-coupled receptor signaling pathway / locomotory behavior / acrosomal vesicle / axon terminus / excitatory postsynaptic potential
Similarity search - Function
Dopamine D2 receptor / Dopamine receptor family / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / G-protein alpha subunit, group I / 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 / 7 Propeller / Methylamine Dehydrogenase; Chain H / 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 / Guanine nucleotide-binding protein, beta subunit / G protein beta WD-40 repeat protein / 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 / Dopamine receptor D2 / 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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