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Yorodumi- PDB-9f33: Cryo-EM structure of Dopamine 3 Receptor:Go complex bound to bito... -
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-Basic information
Entry | Database: PDB / ID: 9f33 | ||||||
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Title | Cryo-EM structure of Dopamine 3 Receptor:Go complex bound to bitopic FOB02-04A - Conformation A | ||||||
Components |
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Keywords | MEMBRANE PROTEIN / GPCR / dopamine / bitopic / receptor | ||||||
Function / homology | Function and homology information musculoskeletal movement, spinal reflex action / acid secretion / dopamine neurotransmitter receptor activity, coupled via Gi/Go / response to histamine / regulation of potassium ion transport / adenylate cyclase-inhibiting dopamine receptor signaling pathway / Dopamine receptors / regulation of dopamine uptake involved in synaptic transmission / positive regulation of dopamine receptor signaling pathway / phospholipase C-activating dopamine receptor signaling pathway ...musculoskeletal movement, spinal reflex action / acid secretion / dopamine neurotransmitter receptor activity, coupled via Gi/Go / response to histamine / regulation of potassium ion transport / adenylate cyclase-inhibiting dopamine receptor signaling pathway / Dopamine receptors / regulation of dopamine uptake involved in synaptic transmission / positive regulation of dopamine receptor signaling pathway / phospholipase C-activating dopamine receptor signaling pathway / negative regulation of oligodendrocyte differentiation / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / negative regulation of synaptic transmission, glutamatergic / G protein-coupled receptor internalization / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor / Sensory perception of sweet, bitter, and umami (glutamate) taste / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / Ca2+ pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G alpha (z) signalling events / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / vesicle docking involved in exocytosis / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / response to morphine / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (i) signalling events / alkylglycerophosphoethanolamine phosphodiesterase activity / photoreceptor outer segment membrane / arachidonate secretion / G protein-coupled dopamine receptor signaling pathway / regulation of heart contraction / spectrin binding / regulation of dopamine secretion / negative regulation of cytosolic calcium ion concentration / dopamine metabolic process / adenylate cyclase-activating adrenergic receptor signaling pathway / positive regulation of cytokinesis / behavioral response to cocaine / social behavior / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / photoreceptor outer segment / negative regulation of protein secretion / negative regulation of insulin secretion / prepulse inhibition / G protein-coupled serotonin receptor binding / muscle contraction / cardiac muscle cell apoptotic process / negative regulation of blood pressure / photoreceptor inner segment / positive regulation of mitotic nuclear division / G-protein beta/gamma-subunit complex binding / bioluminescence / learning / generation of precursor metabolites and energy / response to cocaine / locomotory behavior / G protein-coupled receptor activity / circadian regulation of gene expression / visual learning / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Glucagon signaling in metabolic regulation / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G beta:gamma signalling through CDC42 / Vasopressin regulates renal water homeostasis via Aquaporins / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Glucagon-type ligand receptors / G alpha (z) signalling events / Adrenaline,noradrenaline inhibits insulin secretion / intracellular calcium ion homeostasis / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / GPER1 signaling / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / signaling receptor complex adaptor activity Similarity search - Function | ||||||
Biological species | Homo sapiens (human) Rattus norvegicus (Norway rat) Mus musculus (house mouse) Aequorea victoria (jellyfish) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.05 Å | ||||||
Authors | Arroyo-Urea, S. / Garcia-Nafria, J. | ||||||
Funding support | Spain, 1items
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Citation | Journal: Nat Commun / Year: 2024 Title: A bitopic agonist bound to the dopamine 3 receptor reveals a selectivity site. Authors: Sandra Arroyo-Urea / Antonina L Nazarova / Ángela Carrión-Antolí / Alessandro Bonifazi / Francisco O Battiti / Jordy Homing Lam / Amy Hauck Newman / Vsevolod Katritch / Javier García-Nafría / Abstract: Although aminergic GPCRs are the target for ~25% of approved drugs, developing subtype selective drugs is a major challenge due to the high sequence conservation at their orthosteric binding site. ...Although aminergic GPCRs are the target for ~25% of approved drugs, developing subtype selective drugs is a major challenge due to the high sequence conservation at their orthosteric binding site. Bitopic ligands are covalently joined orthosteric and allosteric pharmacophores with the potential to boost receptor selectivity and improve current medications by reducing off-target side effects. However, the lack of structural information on their binding mode impedes rational design. Here we determine the cryo-EM structure of the hDR:Gαβγ complex bound to the DR selective bitopic agonist FOB02-04A. Structural, functional and computational analyses provide insights into its binding mode and point to a new TM2-ECL1-TM1 region, which requires the N-terminal ordering of TM1, as a major determinant of subtype selectivity in aminergic GPCRs. This region is underexploited in drug development, expands the established secondary binding pocket in aminergic GPCRs and could potentially be used to design novel and subtype selective drugs. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 9f33.cif.gz | 244.7 KB | Display | PDBx/mmCIF format |
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PDB format | pdb9f33.ent.gz | Display | PDB format | |
PDBx/mmJSON format | 9f33.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 9f33_validation.pdf.gz | 1.1 MB | Display | wwPDB validaton report |
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Full document | 9f33_full_validation.pdf.gz | 1.1 MB | Display | |
Data in XML | 9f33_validation.xml.gz | 41.6 KB | Display | |
Data in CIF | 9f33_validation.cif.gz | 61.5 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/f3/9f33 ftp://data.pdbj.org/pub/pdb/validation_reports/f3/9f33 | HTTPS FTP |
-Related structure data
Related structure data | 50168MC 9f34C M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABC
#1: Protein | Mass: 40097.500 Da / Num. of mol.: 1 / Mutation: S47N, G204A, E246A, M249K,A326S Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNAO1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P09471 |
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#2: Protein | Mass: 39373.992 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Gnb1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P54311 |
#3: Protein | Mass: 7845.078 Da / Num. of mol.: 1 / Mutation: C68S 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 |
-Antibody / Protein / Non-polymers , 3 types, 3 molecules ER
#4: Antibody | Mass: 28944.244 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) |
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#5: Protein | Mass: 74733.945 Da / Num. of mol.: 1 / Mutation: L119W Source method: isolated from a genetically manipulated source Details: HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R,HASS-FLAG-eGFP-D3R Source: (gene. exp.) Aequorea victoria (jellyfish), (gene. exp.) Homo sapiens (human) Gene: GFP, DRD3 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P42212, UniProt: P35462 |
#6: Chemical | ChemComp-A1H9N / Mass: 433.546 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H31N5O2 / Feature type: SUBJECT OF INVESTIGATION |
-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: D3R:Go protein complex with bitopic FOB02-04A-Conformation A Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT |
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Molecular weight | Value: 0.190 MDa / Experimental value: NO |
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Trichoplusia ni (cabbage looper) |
Buffer solution | pH: 7.4 |
Specimen | Conc.: 2.8 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R0.6/1 |
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 3000 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: COMA FREE |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Electron dose: 50 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K3 (6k x 4k) / Num. of real images: 22655 |
Image scans | Movie frames/image: 50 |
-Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
Particle selection | Num. of particles selected: 19414230 | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.05 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 275383 / Symmetry type: POINT | ||||||||||||||||||||||||
Atomic model building | Protocol: OTHER / Space: REAL | ||||||||||||||||||||||||
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