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Yorodumi- EMDB-19929: Structural basis of D9-THC analog activity at the Cannabinoid 1 r... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-19929 | ||||||||||||
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Title | Structural basis of D9-THC analog activity at the Cannabinoid 1 receptor | ||||||||||||
Map data | |||||||||||||
Sample |
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Keywords | GPCR / Cannabinoid receptor 1 / THC analog complex / MEMBRANE PROTEIN | ||||||||||||
Function / homology | Function and homology information cannabinoid signaling pathway / regulation of penile erection / retrograde trans-synaptic signaling by endocannabinoid / cannabinoid receptor activity / negative regulation of mast cell activation / trans-synaptic signaling by endocannabinoid, modulating synaptic transmission / negative regulation of fatty acid beta-oxidation / regulation of feeding behavior / negative regulation of dopamine secretion / positive regulation of acute inflammatory response to antigenic stimulus ...cannabinoid signaling pathway / regulation of penile erection / retrograde trans-synaptic signaling by endocannabinoid / cannabinoid receptor activity / negative regulation of mast cell activation / trans-synaptic signaling by endocannabinoid, modulating synaptic transmission / negative regulation of fatty acid beta-oxidation / regulation of feeding behavior / negative regulation of dopamine secretion / positive regulation of acute inflammatory response to antigenic stimulus / negative regulation of serotonin secretion / regulation of presynaptic cytosolic calcium ion concentration / negative regulation of action potential / Class A/1 (Rhodopsin-like receptors) / positive regulation of blood pressure / positive regulation of fever generation / regulation of metabolic process / axonal fasciculation / regulation of synaptic transmission, GABAergic / regulation of insulin secretion / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / T cell migration / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / maternal process involved in female pregnancy / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / GABA-ergic synapse / regulation of mitotic spindle organization / cellular response to forskolin / regulation of synaptic transmission, glutamatergic / negative regulation of blood pressure / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / response to nutrient / response to cocaine / Regulation of insulin secretion / G protein-coupled receptor binding / G protein-coupled receptor activity / adenylate cyclase-activating G protein-coupled receptor signaling pathway / response to nicotine / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / 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 / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G beta:gamma signalling through CDC42 / positive regulation of neuron projection development / response to peptide hormone / 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 / 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 / GDP binding / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / heterotrimeric G-protein complex / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / G alpha (12/13) signalling events / extracellular vesicle / actin cytoskeleton / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / glucose homeostasis / retina development in camera-type eye / Ca2+ pathway / presynaptic membrane / phospholipase C-activating G protein-coupled receptor signaling pathway / cell cortex / midbody / G alpha (i) signalling events / growth cone / fibroblast proliferation / G alpha (s) signalling events / spermatogenesis Similarity search - Function | ||||||||||||
Biological species | Homo sapiens (human) / Mus musculus (house mouse) | ||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.9 Å | ||||||||||||
Authors | Thorsen TS / Kulkarni Y / Boggild A / Drace T / Nissen P / Gajhede M / Boesen T / Kastrup JS / Gloriam D | ||||||||||||
Funding support | Denmark, 3 items
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Citation | Journal: Res Sq / Year: 2024 Title: Structural basis of Δ-THC analog activity at the Cannabinoid 1 receptor. Authors: David Gloriam / Thor Thorsen / Yashraj Kulkarni / David Sykes / Andreas Bøggild / Taner Drace / Pattarin Hompluem / Christos Iliopoulos-Tsoutsouvas / Spyros Nikas / Henrik Daver / ...Authors: David Gloriam / Thor Thorsen / Yashraj Kulkarni / David Sykes / Andreas Bøggild / Taner Drace / Pattarin Hompluem / Christos Iliopoulos-Tsoutsouvas / Spyros Nikas / Henrik Daver / Alexandros Makriyannis / Poul Nissen / Michael Gajhede / Dmitry Veprintsev / Thomas Boesen / Jette Kastrup Abstract: Δ-tetrahydrocannabinol (THC) is the principal psychoactive compound derived from the cannabis plant Cannabis sativa and approved for emetic conditions, appetite stimulation and sleep apnea relief. ...Δ-tetrahydrocannabinol (THC) is the principal psychoactive compound derived from the cannabis plant Cannabis sativa and approved for emetic conditions, appetite stimulation and sleep apnea relief. THC's psychoactive actions are mediated primarily by the cannabinoid receptor CB. Here, we determine the cryo-EM structure of HU210, a THC analog and widely used tool compound, bound to CB and its primary transducer, G. We leverage this structure for docking and 1,000 ns molecular dynamics simulations of THC and 10 structural analogs delineating their spatiotemporal interactions at the molecular level. Furthermore, we pharmacologically profile their recruitment of G and β-arrestins and reversibility of binding from an active complex. By combining detailed CB structural information with molecular models and signaling data we uncover the differential spatiotemporal interactions these ligands make to receptors governing potency, efficacy, bias and kinetics. This may help explain the actions of abused substances, advance fundamental receptor activation studies and design better medicines. | ||||||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_19929.map.gz | 21.7 MB | EMDB map data format | |
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Header (meta data) | emd-19929-v30.xml emd-19929.xml | 22.9 KB 22.9 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_19929_fsc.xml | 7.3 KB | Display | FSC data file |
Images | emd_19929.png | 84 KB | ||
Masks | emd_19929_msk_1.map | 42.9 MB | Mask map | |
Filedesc metadata | emd-19929.cif.gz | 7.2 KB | ||
Others | emd_19929_half_map_1.map.gz emd_19929_half_map_2.map.gz | 39.8 MB 39.8 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-19929 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-19929 | HTTPS FTP |
-Validation report
Summary document | emd_19929_validation.pdf.gz | 791.3 KB | Display | EMDB validaton report |
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Full document | emd_19929_full_validation.pdf.gz | 790.9 KB | Display | |
Data in XML | emd_19929_validation.xml.gz | 14.4 KB | Display | |
Data in CIF | emd_19929_validation.cif.gz | 18.7 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-19929 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-19929 | HTTPS FTP |
-Related structure data
Related structure data | 9erxMC 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_19929.map.gz / Format: CCP4 / Size: 42.9 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: 1.10914 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
File | emd_19929_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_19929_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_19929_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
+Entire : HU210/CB1/Gi1 signaling complex
+Supramolecule #1: HU210/CB1/Gi1 signaling complex
+Supramolecule #2: Cannabinoid 1 receptor complexed with a G protein
+Supramolecule #3: Antibody ScFv16
+Macromolecule #1: Guanine nucleotide-binding protein G(i) subunit alpha-1
+Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
+Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
+Macromolecule #4: Cannabinoid receptor 1
+Macromolecule #5: Antibody ScFv16 Fab fragment
+Macromolecule #6: (6aR,10aR)-9-(hydroxymethyl)-6,6-dimethyl-3-(2-methyloctan-2-yl)-...
+Macromolecule #7: water
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 0.85 mg/mL |
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Buffer | pH: 7.4 |
Grid | Model: Quantifoil / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE |
Vitrification | Cryogen name: ETHANE / Instrument: LEICA EM GP |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Specialist optics | Energy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV |
Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average exposure time: 1.5 sec. / Average electron dose: 60.6 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | C2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.6 µm / Nominal magnification: 130000 |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |