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Yorodumi- EMDB-25403: 5-HT2B receptor bound to LSD in complex with beta-arrestin1 obtai... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-25403 | |||||||||
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Title | 5-HT2B receptor bound to LSD in complex with beta-arrestin1 obtained by cryo-electron microscopy (cryoEM) | |||||||||
Map data | Composite cryo-EM map for 5-HT2BR bound to LSD in complex with beta-arrestin1 | |||||||||
Sample |
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Function / homology | Function and homology information angiotensin receptor binding / Activation of SMO / negative regulation of interleukin-8 production / arrestin family protein binding / G protein-coupled receptor internalization / enzyme inhibitor activity / Lysosome Vesicle Biogenesis / positive regulation of Rho protein signal transduction / negative regulation of NF-kappaB transcription factor activity / Golgi Associated Vesicle Biogenesis ...angiotensin receptor binding / Activation of SMO / negative regulation of interleukin-8 production / arrestin family protein binding / G protein-coupled receptor internalization / enzyme inhibitor activity / Lysosome Vesicle Biogenesis / positive regulation of Rho protein signal transduction / negative regulation of NF-kappaB transcription factor activity / Golgi Associated Vesicle Biogenesis / negative regulation of Notch signaling pathway / stress fiber assembly / pseudopodium / negative regulation of interleukin-6 production / positive regulation of receptor internalization / clathrin-coated pit / negative regulation of protein ubiquitination / insulin-like growth factor receptor binding / visual perception / Activated NOTCH1 Transmits Signal to the Nucleus / GTPase activator activity / G protein-coupled receptor binding / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / cytoplasmic vesicle membrane / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / Signaling by BRAF and RAF1 fusions / protein transport / Thrombin signalling through proteinase activated receptors (PARs) / Cargo recognition for clathrin-mediated endocytosis / Clathrin-mediated endocytosis / cytoplasmic vesicle / ubiquitin-dependent protein catabolic process / G alpha (s) signalling events / proteasome-mediated ubiquitin-dependent protein catabolic process / transcription coactivator activity / positive regulation of ERK1 and ERK2 cascade / nuclear body / Ub-specific processing proteases / protein ubiquitination / positive regulation of protein phosphorylation / Golgi membrane / lysosomal membrane / ubiquitin protein ligase binding / chromatin / regulation of transcription by RNA polymerase II / signal transduction / positive regulation of transcription by RNA polymerase II / nucleoplasm / nucleus / plasma membrane / cytosol / cytoplasm Similarity search - Function | |||||||||
Biological species | Mus musculus (house mouse) / Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.3 Å | |||||||||
Authors | Barros-Alvarez X / Cao C / Panova O / Roth BL / Skiniotis G | |||||||||
Funding support | 1 items
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Citation | Journal: Neuron / Year: 2022 Title: Signaling snapshots of a serotonin receptor activated by the prototypical psychedelic LSD. Authors: Can Cao / Ximena Barros-Álvarez / Shicheng Zhang / Kuglae Kim / Marc A Dämgen / Ouliana Panova / Carl-Mikael Suomivuori / Jonathan F Fay / Xiaofang Zhong / Brian E Krumm / Ryan H Gumpper / ...Authors: Can Cao / Ximena Barros-Álvarez / Shicheng Zhang / Kuglae Kim / Marc A Dämgen / Ouliana Panova / Carl-Mikael Suomivuori / Jonathan F Fay / Xiaofang Zhong / Brian E Krumm / Ryan H Gumpper / Alpay B Seven / Michael J Robertson / Nevan J Krogan / Ruth Hüttenhain / David E Nichols / Ron O Dror / Georgios Skiniotis / Bryan L Roth / Abstract: Serotonin (5-hydroxytryptamine [5-HT]) 5-HT2-family receptors represent essential targets for lysergic acid diethylamide (LSD) and all other psychedelic drugs. Although the primary psychedelic drug ...Serotonin (5-hydroxytryptamine [5-HT]) 5-HT2-family receptors represent essential targets for lysergic acid diethylamide (LSD) and all other psychedelic drugs. Although the primary psychedelic drug effects are mediated by the 5-HT serotonin receptor (HTR2A), the 5-HT serotonin receptor (HTR2B) has been used as a model receptor to study the activation mechanisms of psychedelic drugs due to its high expression and similarity to HTR2A. In this study, we determined the cryo-EM structures of LSD-bound HTR2B in the transducer-free, Gq-protein-coupled, and β-arrestin-1-coupled states. These structures provide distinct signaling snapshots of LSD's action, ranging from the transducer-free, partially active state to the transducer-coupled, fully active states. Insights from this study will both provide comprehensive molecular insights into the signaling mechanisms of the prototypical psychedelic LSD and accelerate the discovery of novel psychedelic drugs. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_25403.map.gz | 1.6 MB | EMDB map data format | |
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Header (meta data) | emd-25403-v30.xml emd-25403.xml | 22.6 KB 22.6 KB | Display Display | EMDB header |
Images | emd_25403.png | 77.6 KB | ||
Others | emd_25403_additional_1.map.gz emd_25403_additional_2.map.gz | 1.3 MB 1.3 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-25403 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-25403 | HTTPS FTP |
-Related structure data
Related structure data | 7srsMC 7srqC 7srrC 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_25403.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Annotation | Composite cryo-EM map for 5-HT2BR bound to LSD in complex with beta-arrestin1 | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.8521 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Additional map: Focused refinement map for 5-HT2BR bound to LSD...
File | emd_25403_additional_1.map | ||||||||||||
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Annotation | Focused refinement map for 5-HT2BR bound to LSD and a scFv fragment of anti-5HT2BR Fab | ||||||||||||
Projections & Slices |
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Density Histograms |
-Additional map: Focused refinement map for beta-arrestin1, scFv30 and 5HT2BR C-tail
File | emd_25403_additional_2.map | ||||||||||||
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Annotation | Focused refinement map for beta-arrestin1, scFv30 and 5HT2BR C-tail | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
-Entire : 5-HT2B receptor bound to LSD in complex with beta-arrestin1
Entire | Name: 5-HT2B receptor bound to LSD in complex with beta-arrestin1 |
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Components |
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-Supramolecule #1: 5-HT2B receptor bound to LSD in complex with beta-arrestin1
Supramolecule | Name: 5-HT2B receptor bound to LSD in complex with beta-arrestin1 type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1-#6 |
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-Macromolecule #1: Anti-5HT2BR Fab light chain
Macromolecule | Name: Anti-5HT2BR Fab light chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Mus musculus (house mouse) |
Molecular weight | Theoretical: 22.719348 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: DIVLIQSPAI MSASPGEKVT ITCSASSSVS YMHWFQQKPG TSPKLWIYST SNLASGVPAR FSGSGSGTSY SLTISRMEAE DAATYYCQQ RSSYPLTFGA GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ E SVTEQDSK ...String: DIVLIQSPAI MSASPGEKVT ITCSASSSVS YMHWFQQKPG TSPKLWIYST SNLASGVPAR FSGSGSGTSY SLTISRMEAE DAATYYCQQ RSSYPLTFGA GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ E SVTEQDSK DSTYSLSSTL TLSKADYEKH KVYACEVTHQ GLPVTKSFNR G |
-Macromolecule #2: Anti-5HT2BR Fab heavy chain
Macromolecule | Name: Anti-5HT2BR Fab heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Mus musculus (house mouse) |
Molecular weight | Theoretical: 23.48732 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: EVQLQQSGPE LVKPGASVKL SCKASGYTFT SSWMHWVKQR PGQGLEWIGN IYPSNGGTNY NERFKSKATL TVDRSSNTAY MQLSSLTSE DSAVYFCARF GSFITTILTT YYNPVDYWGQ GTTLTVSSAS TKGPSVFPLA PSTAALGCLV KDYFPEPVTV S WNSGALTS ...String: EVQLQQSGPE LVKPGASVKL SCKASGYTFT SSWMHWVKQR PGQGLEWIGN IYPSNGGTNY NERFKSKATL TVDRSSNTAY MQLSSLTSE DSAVYFCARF GSFITTILTT YYNPVDYWGQ GTTLTVSSAS TKGPSVFPLA PSTAALGCLV KDYFPEPVTV S WNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPASSLGT QTYICNVNHK PSNTKVDKKV |
-Macromolecule #3: 5-hydroxytryptamine receptor 2B
Macromolecule | Name: 5-hydroxytryptamine receptor 2B / 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: 37.722496 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: TESIPEEMKQ IVEEQGNKLH WAALLILMVI IPTIGGNTLV ILAVSLEKKL QYATNYFLMS LAVADLLVGL FVMPIALLTI MFEAMWPLP LVLCPAWLFL DVLFSTASIW HLCAISVDRY IAIKKPIQAN QYNSRATAFI KITVVWLISI GIAIPVPIKG I ETDVDNPN ...String: TESIPEEMKQ IVEEQGNKLH WAALLILMVI IPTIGGNTLV ILAVSLEKKL QYATNYFLMS LAVADLLVGL FVMPIALLTI MFEAMWPLP LVLCPAWLFL DVLFSTASIW HLCAISVDRY IAIKKPIQAN QYNSRATAFI KITVVWLISI GIAIPVPIKG I ETDVDNPN NITCVLTKER FGDFMLFGSL AAFFTPLAIM IVTYFLTIHA LQKVRLLSGS RQTISNLQRA SKVLGIVFFL FL LMWCPFF ITNITLVLCD SCNQTTLQML LEIFVWIGYV SSGVNPLVYT LFNKTFRDAF GRYITCNYRA TKSVKTPMRL RSS TIQ(SEP)(SEP)(SEP) IILLDTL |
-Macromolecule #4: Isoform 1B of Beta-arrestin-1
Macromolecule | Name: Isoform 1B of Beta-arrestin-1 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 41.345305 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: GDKGTRVFKK ASPNGKLTVY LGKRDFVDHI DLVDPVDGVV LVDPEYLKER RVYVTLTCAF RYGREDLDVL GLTFRKDLFV ANVQSFPPA PEDKKPLTRL QERLIKKLGE HAYPFTFEIP PNLPCSVTLQ PGPEDTGKAC GVDYEVKAFC AENLEEKIHK R NSVRLVIE ...String: GDKGTRVFKK ASPNGKLTVY LGKRDFVDHI DLVDPVDGVV LVDPEYLKER RVYVTLTCAF RYGREDLDVL GLTFRKDLFV ANVQSFPPA PEDKKPLTRL QERLIKKLGE HAYPFTFEIP PNLPCSVTLQ PGPEDTGKAC GVDYEVKAFC AENLEEKIHK R NSVRLVIE KVQYAPERPG PQPTAETTRQ FLMSDKPLHL EASLDKEIYY HGEPISVNVH VTNNTNKTVK KIKISVRQYA DI CLFNTAQ YKCPVAMEEA DDTVAPSSTF CKVYTLTPFL ANNREKRGLA LDGKLKHEDT NLASSTLLRE GANREILGII VSY KVKVKL VVSRGGDVAV ELPFTLMHPK PKEEPPHREV PENETPVDTN L |
-Macromolecule #5: Fab30 heavy chain
Macromolecule | Name: Fab30 heavy chain / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Mus musculus (house mouse) |
Molecular weight | Theoretical: 13.063479 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: VQLVESGGGL VQPGGSLRLS CAASGFNVYS SSIHWVRQAP GKGLRWVASI SSYYGYTYYA DSVKGRFTIS ADTSKNTAYL QMNSLRAED TAVYYCARSR QFWYSGLDYW GQGTLVTVSS |
-Macromolecule #6: Fab30 light chain
Macromolecule | Name: Fab30 light chain / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Mus musculus (house mouse) |
Molecular weight | Theoretical: 11.50082 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: DIQMTQSPSS LSASVGDRVT ITCRASQSVS SAVAWYQQKP GKAPKLLIYS ASSLYSGVPS RFSGSRSGTD FTLTISSLQP EDFATYYCQ QYKYVPVTFG QGTKVEI |
-Macromolecule #7: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 7 / Number of copies: 1 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ChemComp-NAG: |
-Macromolecule #8: (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: 8 / 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 |
-Sample preparation
Concentration | 3.5 mg/mL |
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Buffer | pH: 7.5 |
Vitrification | Cryogen name: ETHANE / 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) / Average electron dose: 1.36 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | C2 aperture diameter: 70.0 µm / Calibrated magnification: 57050 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.8 µm |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |