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Yorodumi- EMDB-32965: Cryo-EM structure of the tavapadon-bound D1 dopamine receptor and... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-32965 | |||||||||
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Title | Cryo-EM structure of the tavapadon-bound D1 dopamine receptor and mini-Gs complex | |||||||||
Map data | ||||||||||
Sample |
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Function / homology | Function and homology information dopamine neurotransmitter receptor activity, coupled via Gs / dopamine neurotransmitter receptor activity / cerebral cortex GABAergic interneuron migration / operant conditioning / Dopamine receptors / modification of postsynaptic structure / regulation of dopamine uptake involved in synaptic transmission / dopamine binding / heterotrimeric G-protein binding / positive regulation of neuron migration ...dopamine neurotransmitter receptor activity, coupled via Gs / dopamine neurotransmitter receptor activity / cerebral cortex GABAergic interneuron migration / operant conditioning / Dopamine receptors / modification of postsynaptic structure / regulation of dopamine uptake involved in synaptic transmission / dopamine binding / heterotrimeric G-protein binding / positive regulation of neuron migration / G protein-coupled receptor complex / peristalsis / regulation of dopamine metabolic process / sensitization / phospholipase C-activating dopamine receptor signaling pathway / grooming behavior / habituation / dopamine transport / astrocyte development / positive regulation of potassium ion transport / conditioned taste aversion / striatum development / dentate gyrus development / maternal behavior / arrestin family protein binding / non-motile cilium / adult walking behavior / long-term synaptic depression / mating behavior / ciliary membrane / G protein-coupled dopamine receptor signaling pathway / temperature homeostasis / activation of adenylate cyclase activity / dopamine metabolic process / D-glucose import / transmission of nerve impulse / adenylate cyclase-activating adrenergic receptor signaling pathway / behavioral response to cocaine / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / neuronal action potential / G-protein alpha-subunit binding / behavioral fear response / prepulse inhibition / GABA-ergic synapse / synapse assembly / presynaptic modulation of chemical synaptic transmission / response to amphetamine / positive regulation of synaptic transmission, glutamatergic / positive regulation of release of sequestered calcium ion into cytosol / synaptic transmission, glutamatergic / G protein-coupled receptor activity / long-term synaptic potentiation / adenylate cyclase-activating G protein-coupled receptor signaling pathway / regulation of protein phosphorylation / visual learning / Olfactory Signaling Pathway / Activation of the phototransduction cascade / 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-coupled acetylcholine receptor signaling pathway / G-protein activation / cilium / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G beta:gamma signalling through CDC42 / memory / Vasopressin regulates renal water homeostasis via Aquaporins / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / G alpha (z) signalling events / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / vasodilation / sensory perception of taste / protein import into nucleus / 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 / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / Ca2+ pathway Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) / synthetic construct (others) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.3 Å | |||||||||
Authors | Teng X / Zheng S | |||||||||
Funding support | China, 1 items
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Citation | Journal: Nat Commun / Year: 2022 Title: Ligand recognition and biased agonism of the D1 dopamine receptor. Authors: Xiao Teng / Sijia Chen / Yingying Nie / Peng Xiao / Xiao Yu / Zhenhua Shao / Sanduo Zheng / Abstract: Dopamine receptors are widely distributed in the central nervous system and are important therapeutic targets for treatment of various psychiatric and neurological diseases. Here, we report three ...Dopamine receptors are widely distributed in the central nervous system and are important therapeutic targets for treatment of various psychiatric and neurological diseases. Here, we report three cryo-electron microscopy structures of the D1 dopamine receptor (D1R)-Gs complex bound to two agonists, fenoldopam and tavapadon, and a positive allosteric modulator LY3154207. The structure reveals unusual binding of two fenoldopam molecules, one to the orthosteric binding pocket (OBP) and the other to the extended binding pocket (EBP). In contrast, one elongated tavapadon molecule binds to D1R, extending from OBP to EBP. Moreover, LY3154207 stabilizes the second intracellular loop of D1R in an alpha helical conformation to efficiently engage the G protein. Through a combination of biochemical, biophysical and cellular assays, we further show that the broad conformation stabilized by two fenoldopam molecules and interaction between TM5 and the agonist are important for biased signaling of D1R. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_32965.map.gz | 20.9 MB | EMDB map data format | |
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Header (meta data) | emd-32965-v30.xml emd-32965.xml | 17.6 KB 17.6 KB | Display Display | EMDB header |
Images | emd_32965.png | 32.1 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-32965 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-32965 | HTTPS FTP |
-Validation report
Summary document | emd_32965_validation.pdf.gz | 425.5 KB | Display | EMDB validaton report |
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Full document | emd_32965_full_validation.pdf.gz | 425.1 KB | Display | |
Data in XML | emd_32965_validation.xml.gz | 5.7 KB | Display | |
Data in CIF | emd_32965_validation.cif.gz | 6.4 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-32965 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-32965 | HTTPS FTP |
-Related structure data
Related structure data | 7x2dMC 7x2cC 7x2fC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_32965.map.gz / Format: CCP4 / Size: 22.2 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.087 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Sample components
+Entire : Cryo-EM structure of the tavapadon-bound D1R-miniGs complex
+Supramolecule #1: Cryo-EM structure of the tavapadon-bound D1R-miniGs complex
+Supramolecule #2: tavapadon-bound D1R-miniGs
+Supramolecule #3: nanobody35
+Macromolecule #1: D(1A) dopamine receptor
+Macromolecule #2: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
+Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
+Macromolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
+Macromolecule #5: Nanobody35
+Macromolecule #6: CHOLESTEROL
+Macromolecule #7: 1,5-dimethyl-6-[2-methyl-4-[3-(trifluoromethyl)pyridin-2-yl]oxy-p...
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 4.0 mg/mL |
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Buffer | pH: 7.5 |
Grid | Model: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 281 K / Instrument: FEI VITROBOT MARK IV |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number real images: 1861 / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.7000000000000001 µm / Nominal magnification: 64000 |
Sample stage | Cooling holder cryogen: NITROGEN |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |