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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 | |||||||||
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Function / homology | Function and homology information dopamine neurotransmitter receptor activity / cerebral cortex GABAergic interneuron migration / Dopamine receptors / operant conditioning / dopamine neurotransmitter receptor activity, coupled via Gs / dopamine binding / regulation of dopamine uptake involved in synaptic transmission / modification of postsynaptic structure / heterotrimeric G-protein binding / regulation of dopamine metabolic process ...dopamine neurotransmitter receptor activity / cerebral cortex GABAergic interneuron migration / Dopamine receptors / operant conditioning / dopamine neurotransmitter receptor activity, coupled via Gs / dopamine binding / regulation of dopamine uptake involved in synaptic transmission / modification of postsynaptic structure / heterotrimeric G-protein binding / regulation of dopamine metabolic process / sensitization / peristalsis / G protein-coupled receptor complex / dopamine transport / phospholipase C-activating dopamine receptor signaling pathway / grooming behavior / positive regulation of neuron migration / habituation / astrocyte development / conditioned taste aversion / positive regulation of potassium ion transport / striatum development / dentate gyrus development / maternal behavior / arrestin family protein binding / non-motile cilium / adult walking behavior / mating behavior / long-term synaptic depression / ciliary membrane / G protein-coupled dopamine receptor signaling pathway / temperature homeostasis / dopamine metabolic process / transmission of nerve impulse / glucose import / behavioral response to cocaine / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / G-protein alpha-subunit binding / GABA-ergic synapse / neuronal action potential / behavioral fear response / prepulse inhibition / adenylate cyclase-activating adrenergic receptor signaling pathway / synapse assembly / response to amphetamine / activation of adenylate cyclase activity / presynaptic modulation of chemical synaptic transmission / 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 / regulation of protein phosphorylation / visual learning / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G-protein activation / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / memory / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / cilium / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / vasodilation / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / protein import into nucleus / GPER1 signaling / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / 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 / presynaptic membrane 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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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 |