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Yorodumi- EMDB-44866: Global reconstruction of DRD2 bound to LSD in complex with a mini... -
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Basic information
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| Title | Global reconstruction of DRD2 bound to LSD in complex with a mini-GoA and scFv16 obtained by cryo-electron microscopy (cryoEM) | |||||||||
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Keywords | GPCR / G-protein Coupled Receptor / DRD2 / serotonin / psychedelics / MEMBRANE PROTEIN | |||||||||
| Function / homology | Function and homology informationnegative regulation of dopamine receptor signaling pathway / positive regulation of dopamine uptake involved in synaptic transmission / negative regulation of dephosphorylation / positive regulation of glial cell-derived neurotrophic factor production / acid secretion / nervous system process involved in regulation of systemic arterial blood pressure / regulation of synapse structural plasticity / dopamine neurotransmitter receptor activity, coupled via Gi/Go / response to histamine / negative regulation of circadian sleep/wake cycle, sleep ...negative regulation of dopamine receptor signaling pathway / positive regulation of dopamine uptake involved in synaptic transmission / negative regulation of dephosphorylation / positive regulation of glial cell-derived neurotrophic factor production / acid secretion / nervous system process involved in regulation of systemic arterial blood pressure / regulation of synapse structural plasticity / dopamine neurotransmitter receptor activity, coupled via Gi/Go / response to histamine / negative regulation of circadian sleep/wake cycle, sleep / regulation of locomotion involved in locomotory behavior / neuron-neuron synaptic transmission / negative regulation of cellular response to hypoxia / adenylate cyclase-inhibiting dopamine receptor signaling pathway / response to inactivity / regulation of potassium ion transport / orbitofrontal cortex development / negative regulation of dopamine secretion / adenohypophysis development / cerebral cortex GABAergic interneuron migration / negative regulation of neuron migration / hyaloid vascular plexus regression / Dopamine receptors / branching morphogenesis of a nerve / regulation of dopamine uptake involved in synaptic transmission / dopamine binding / positive regulation of growth hormone secretion / phospholipase C-activating dopamine receptor signaling pathway / heterotrimeric G-protein binding / peristalsis / beta-arrestin-dependent dopamine receptor signaling pathway / G protein-coupled receptor complex / grooming behavior / positive regulation of renal sodium excretion / drinking behavior / striatum development / auditory behavior / positive regulation of G protein-coupled receptor signaling pathway / dopaminergic synapse / mu-type opioid receptor binding / vesicle docking involved in exocytosis / behavioral response to ethanol / corticotropin-releasing hormone receptor 1 binding / positive regulation of multicellular organism growth / non-motile cilium / G protein-coupled receptor internalization / response to iron ion / G protein-coupled dopamine receptor signaling pathway / adult walking behavior / negative regulation of synaptic transmission, glutamatergic / arachidonate secretion / positive regulation of urine volume / ciliary membrane / positive regulation of neuroblast proliferation / regulation of synaptic transmission, GABAergic / positive regulation of cytokinesis / response to morphine / negative regulation of cytosolic calcium ion concentration / temperature homeostasis / regulation of heart contraction / pigmentation / dopamine metabolic process / dopamine uptake involved in synaptic transmission / regulation of dopamine secretion / parallel fiber to Purkinje cell synapse / positive regulation of receptor internalization / neuroblast proliferation / lateral plasma membrane / negative regulation of protein secretion / associative learning / cellular response to ethanol / response to light stimulus / potassium channel regulator activity / endocytic vesicle / G-protein alpha-subunit binding / response to axon injury / sperm flagellum / postsynaptic modulation of chemical synaptic transmission / long-term memory / prepulse inhibition / regulation of sodium ion transport / cellular response to retinoic acid / negative regulation of blood pressure / behavioral response to cocaine / release of sequestered calcium ion into cytosol / synapse assembly / adenylate cyclase-inhibiting serotonin receptor signaling pathway / axonogenesis / G protein-coupled serotonin receptor binding / epithelial cell proliferation / regulation of heart rate / negative regulation of innate immune response / ionotropic glutamate receptor binding / axon terminus / muscle contraction / acrosomal vesicle / negative regulation of cell migration / presynaptic modulation of chemical synaptic transmission / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of long-term synaptic potentiation Similarity search - Function | |||||||||
| Biological species | Homo sapiens (human) / ![]() | |||||||||
| Method | single particle reconstruction / cryo EM / Resolution: 2.32 Å | |||||||||
Authors | Kim K / Gumpper RH / Fay JF / Roth BL | |||||||||
| Funding support | United States, 1 items
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Citation | Journal: Neuron / Year: 2025Title: The polypharmacology of psychedelics reveals multiple targets for potential therapeutics. Authors: Manish K Jain / Ryan H Gumpper / Samuel T Slocum / Gavin P Schmitz / Jakob S Madsen / Tia A Tummino / Carl-Mikael Suomivuori / Xi-Ping Huang / Laura Shub / Jeffrey F DiBerto / Kuglae Kim / ...Authors: Manish K Jain / Ryan H Gumpper / Samuel T Slocum / Gavin P Schmitz / Jakob S Madsen / Tia A Tummino / Carl-Mikael Suomivuori / Xi-Ping Huang / Laura Shub / Jeffrey F DiBerto / Kuglae Kim / Chelsea DeLeon / Brain E Krumm / Jonathan F Fay / Michael Keiser / Alexander S Hauser / Ron O Dror / Brian Shoichet / David E Gloriam / David E Nichols / Bryan L Roth / ![]() Abstract: The classical psychedelics (+)-lysergic acid diethylamide (LSD), psilocybin, and mescaline exert their psychedelic effects via activation of the 5-HT serotonin receptor (5-HTR). Recent clinical ...The classical psychedelics (+)-lysergic acid diethylamide (LSD), psilocybin, and mescaline exert their psychedelic effects via activation of the 5-HT serotonin receptor (5-HTR). Recent clinical studies have suggested that classical psychedelics may additionally have therapeutic potential for many neuropsychiatric conditions including depression, anxiety, migraine and cluster headaches, drug abuse, and post-traumatic stress disorder. In this study, we investigated the pharmacology of 41 classical psychedelics from the tryptamine, phenethylamine, and lysergamide chemical classes. We profiled these compounds against 318 human G-protein-coupled receptors (GPCRs) to elucidate their target profiles, and in the case of LSD, against more than 450 human kinases. We found that psychedelics have potent and efficacious actions at nearly every serotonin, dopamine, and adrenergic receptor. We quantified their activation for multiple transducers and found that psychedelics stimulate multiple 5-HTR transducers, each of which correlates with psychedelic drug-like actions in vivo. Our results suggest that multiple molecular targets likely contribute to the actions of psychedelics. | |||||||||
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Structure visualization
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Downloads & links
-EMDB archive
| Map data | emd_44866.map.gz | 85.2 MB | EMDB map data format | |
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| Header (meta data) | emd-44866-v30.xml emd-44866.xml | 23.1 KB 23.1 KB | Display Display | EMDB header |
| Images | emd_44866.png | 54.5 KB | ||
| Masks | emd_44866_msk_1.map | 91.1 MB | Mask map | |
| Filedesc metadata | emd-44866.cif.gz | 7.4 KB | ||
| Others | emd_44866_half_map_1.map.gz emd_44866_half_map_2.map.gz | 84.5 MB 84.5 MB | ||
| Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-44866 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-44866 | HTTPS FTP |
-Related structure data
| Related structure data | ![]() 9bsbMC ![]() 9bs9C M: atomic model generated by this map C: citing same article ( |
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| Similar structure data | Similarity search - Function & homology F&H Search |
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Links
| EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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| Related items in Molecule of the Month |
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Map
| File | Download / File: emd_44866.map.gz / Format: CCP4 / Size: 91.1 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: 0.88 Å | ||||||||||||||||||||||||||||||||||||
| Density |
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| Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
| Details | EMDB XML:
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-Supplemental data
-Mask #1
| File | emd_44866_msk_1.map | ||||||||||||
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-Half map: #2
| File | emd_44866_half_map_1.map | ||||||||||||
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| Density Histograms |
-Half map: #1
| File | emd_44866_half_map_2.map | ||||||||||||
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Sample components
-Entire : DRD2 in complex mini-GoA
| Entire | Name: DRD2 in complex mini-GoA |
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| Components |
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-Supramolecule #1: DRD2 in complex mini-GoA
| Supramolecule | Name: DRD2 in complex mini-GoA / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #3, #1-#2, #4-#5 |
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| Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
| Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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| Source (natural) | Organism: Homo sapiens (human) |
| Molecular weight | Theoretical: 38.146707 KDa |
| Recombinant expression | Organism: ![]() |
| Sequence | String: MGSLLQSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG YLSCCRFLDD N QIVTSSGD ...String: MGSLLQSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG YLSCCRFLDD N QIVTSSGD TTCALWDIET GQQTTTFTGH TGDVMSLSLA PDTRLFVSGA CDASAKLWDV REGMCRQTFT GHESDINAIC FF PNGNAFA TGSDDATCRL FDLRADQELM TYSHDNIICG ITSVSFSKSG RLLLAGYDDF NCNVWDALKA DRAGVLAGHD NRV SCLGVT DDGMAVATGS WDSFLKIWNG SS UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 |
-Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
| Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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| Source (natural) | Organism: Homo sapiens (human) |
| Molecular weight | Theoretical: 7.861143 KDa |
| Recombinant expression | Organism: ![]() |
| Sequence | String: MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 |
-Macromolecule #3: Soluble cytochrome b562,D(2) dopamine receptor
| Macromolecule | Name: Soluble cytochrome b562,D(2) dopamine receptor / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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| Source (natural) | Organism: Homo sapiens (human) |
| Molecular weight | Theoretical: 67.234578 KDa |
| Recombinant expression | Organism: ![]() |
| Sequence | String: DYKDDDDAKL QTMHHHHHHH HHHHHHHHAD LEDNWETLND NLKVIEKADN AAQVKDALTK MRAAALDAQK ATPPKLEDKS PDSPEMKDF RHGFDILVGQ IDDALKLANE GKVKEAQAAA EQLKTTRNAY IQKYLASENL YFQGGTMDPL NLSWYDDDLE R QNWSRPFN ...String: DYKDDDDAKL QTMHHHHHHH HHHHHHHHAD LEDNWETLND NLKVIEKADN AAQVKDALTK MRAAALDAQK ATPPKLEDKS PDSPEMKDF RHGFDILVGQ IDDALKLANE GKVKEAQAAA EQLKTTRNAY IQKYLASENL YFQGGTMDPL NLSWYDDDLE R QNWSRPFN GSDGKADRPH YNYYATLLTL LIAVIVFGNV LVCMAVSREK ALQTTTNYLI VSLAVADLLV ATLVMPWVVY LE VVGEWKF SRIHCDIFVT LDVMMCTASI LNLCAISIDR YTAVAMPMLY NTRYSSKRRV TVMISIVWVL SFTISCPLLF GLN NADQNE CIIANPAFVV YSSIVSFYVP FIVTLLVYIK IYIVLRRRRK RVNTKRSSRA FRAHLRAPLK GNCTHPEDMK LCTV IMKSN GSFPVNRRRV EAARRAQELE MEMLSSTSPP ERTRYSPIPP SHHQLTLPDP SHHGLHSTPD SPAKPEKNGH AKDHP KIAK IFEIQTMPNG KTRTSLKTMS RRKLSQQKEK KATQMLAIVL GVFIICWLPF FITHILNIHC DCNIPPVLYS AFTWLG YVN SAVNPIIYTT FNIEFRKAFL KILHC UniProtKB: Soluble cytochrome b562, D(2) dopamine receptor |
-Macromolecule #4: Single chain Fab 16 (scFv16)
| Macromolecule | Name: Single chain Fab 16 (scFv16) / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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| Source (natural) | Organism: ![]() |
| Molecular weight | Theoretical: 28.674902 KDa |
| Recombinant expression | Organism: ![]() |
| Sequence | String: DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS ...String: DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS NGNTYLYWFL QRPGQSPQLL IYRMSNLASG VPDRFSGSGS GTAFTLTISR LEAEDVGVYY CMQHLEYPLT FG AGTKLEL KGSLEVLFQG PAAAHHHHHH H |
-Macromolecule #5: Guanine nucleotide-binding protein G(o) subunit alpha
| Macromolecule | Name: Guanine nucleotide-binding protein G(o) subunit alpha / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO |
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| Source (natural) | Organism: Homo sapiens (human) |
| Molecular weight | Theoretical: 40.22157 KDa |
| Recombinant expression | Organism: ![]() |
| Sequence | String: MGCTLSAEDK AAVERSKMIE KNLKEDGISA AKDVKLLLLG ADNSGKSTIV KQMKIIHEDG FSGEDVKQYK PVVYSNTIQS LAAIVRAMD TLGIEYGDKE RKADAKMVCD VVSRMEDTEP FSAELLSAMM RLWGDSGIQE CFNRSREYQL NDSAKYYLDS L DRIGAADY ...String: MGCTLSAEDK AAVERSKMIE KNLKEDGISA AKDVKLLLLG ADNSGKSTIV KQMKIIHEDG FSGEDVKQYK PVVYSNTIQS LAAIVRAMD TLGIEYGDKE RKADAKMVCD VVSRMEDTEP FSAELLSAMM RLWGDSGIQE CFNRSREYQL NDSAKYYLDS L DRIGAADY QPTEQDILRT RVKTTGIVET HFTFKNLHFR LFDVGGQRSE RKKWIHCFED VTAIIFCVDL SDYDQVLHED ET TNRMHES LMLFDSICNN KFFIDTSIIL FLNKKDLFGE KIKKSPLTIC FPEYTGPNTY EDAAAYIQAQ FESKNRSPNK EIY CHMTCA TDTNNAQVIF DAVTDIIIAN NLRGCGLY UniProtKB: Guanine nucleotide-binding protein G(o) subunit alpha |
-Macromolecule #6: (8alpha)-N,N-diethyl-6-methyl-9,10-didehydroergoline-8-carboxamide
| Macromolecule | Name: (8alpha)-N,N-diethyl-6-methyl-9,10-didehydroergoline-8-carboxamide type: ligand / ID: 6 / Number of copies: 1 / Formula: 7LD |
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| Molecular weight | Theoretical: 323.432 Da |
| Chemical component information | ![]() ChemComp-7LD: |
-Experimental details
-Structure determination
| Method | cryo EM |
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Processing | single particle reconstruction |
| Aggregation state | particle |
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Sample preparation
| Buffer | pH: 7.4 |
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| Vitrification | Cryogen name: ETHANE-PROPANE |
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Electron microscopy
| Microscope | FEI TALOS ARCTICA |
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| Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 49.5 e/Å2 |
| Electron beam | Acceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN |
| Electron optics | Illumination mode: OTHER / Imaging mode: OTHER / Nominal defocus max: 2.6 µm / Nominal defocus min: 0.17 µm |
| Experimental equipment | ![]() Model: Talos Arctica / Image courtesy: FEI Company |
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Keywords
Homo sapiens (human)
Authors
United States, 1 items
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Processing
FIELD EMISSION GUN

