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- EMDB-25402: 5-HT2B receptor bound to LSD in complex with heterotrimeric mini-... -
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Basic information
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Title | 5-HT2B receptor bound to LSD in complex with heterotrimeric mini-Gq protein obtained by cryo-electron microscopy (cryoEM) | |||||||||
![]() | Composite cryo-EM map for 5-HT2BR bound to LSD in complex with heterotrimeric mini-Gq | |||||||||
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Function / homology | ![]() behavior / intestine smooth muscle contraction / Gq/11-coupled serotonin receptor activity / phospholipase C-activating serotonin receptor signaling pathway / positive regulation of phosphatidylinositol biosynthetic process / G protein-coupled serotonin receptor signaling pathway / G protein-coupled serotonin receptor complex / protein kinase C signaling / regulation of behavior / Serotonin receptors ...behavior / intestine smooth muscle contraction / Gq/11-coupled serotonin receptor activity / phospholipase C-activating serotonin receptor signaling pathway / positive regulation of phosphatidylinositol biosynthetic process / G protein-coupled serotonin receptor signaling pathway / G protein-coupled serotonin receptor complex / protein kinase C signaling / regulation of behavior / Serotonin receptors / embryonic morphogenesis / cellular response to temperature stimulus / serotonin binding / vasoconstriction / protein kinase C-activating G protein-coupled receptor signaling pathway / G protein-coupled serotonin receptor activity / G protein-coupled receptor internalization / cardiac muscle hypertrophy / neural crest cell differentiation / neural crest cell migration / neurotransmitter receptor activity / cGMP-mediated signaling / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / positive regulation of cell division / : / G-protein alpha-subunit binding / heart morphogenesis / release of sequestered calcium ion into cytosol / positive regulation of endothelial cell proliferation / ERK1 and ERK2 cascade / GTPase activator activity / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of nitric-oxide synthase activity / positive regulation of cytokine production / calcium-mediated signaling / positive regulation of MAP kinase activity / 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 / 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 / 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 / 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 / intracellular calcium ion homeostasis / 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 / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / 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 / phospholipase C-activating G protein-coupled receptor signaling pathway / Ca2+ pathway / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / chemical synaptic transmission / positive regulation of canonical NF-kappaB signal transduction / cell population proliferation / Ras protein signal transduction / Extra-nuclear estrogen signaling / positive regulation of ERK1 and ERK2 cascade / response to xenobiotic stimulus / G protein-coupled receptor signaling pathway / phosphorylation / lysosomal membrane / GTPase activity / synapse / dendrite / positive regulation of cell population proliferation / protein-containing complex binding / negative regulation of apoptotic process / signal transduction Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.9 Å | |||||||||
![]() | Barros-Alvarez X / Kim K / Panova O / Cao C / Roth BL / Skiniotis G | |||||||||
Funding support | 1 items
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![]() | ![]() 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 | ![]() | 1.5 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 22.1 KB 22.1 KB | Display Display | ![]() |
Images | ![]() | 103.8 KB | ||
Others | ![]() ![]() | 744.2 KB 1.8 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 306.8 KB | Display | ![]() |
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Full document | ![]() | 306.3 KB | Display | |
Data in XML | ![]() | 6.8 KB | Display | |
Data in CIF | ![]() | 7.8 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7srrMC ![]() 7srqC ![]() 7srsC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
File | ![]() | ||||||||||||||||||||
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Annotation | Composite cryo-EM map for 5-HT2BR bound to LSD in complex with heterotrimeric mini-Gq | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.8677 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_25402_additional_1.map | ||||||||||||
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Annotation | Focused refinement map for 5-HT2BR bound to LSD | ||||||||||||
Projections & Slices |
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Density Histograms |
-Additional map: Focused refinement map for heterotrimeric mini-Gq
File | emd_25402_additional_2.map | ||||||||||||
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Annotation | Focused refinement map for heterotrimeric mini-Gq | ||||||||||||
Projections & Slices |
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Density Histograms |
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Sample components
-Entire : 5-HT2B receptor bound to LSD in complex with heterotrimeric mini-...
Entire | Name: 5-HT2B receptor bound to LSD in complex with heterotrimeric mini-Gq protein and single-chain variable fragment (scFv16) |
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Components |
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-Supramolecule #1: 5-HT2B receptor bound to LSD in complex with heterotrimeric mini-...
Supramolecule | Name: 5-HT2B receptor bound to LSD in complex with heterotrimeric mini-Gq protein and single-chain variable fragment (scFv16) type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5 |
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Source (natural) | Organism: ![]() |
Recombinant expression | Organism: ![]() ![]() |
-Macromolecule #1: G protein subunit q (Gi2-mini-Gq chimera)
Macromolecule | Name: G protein subunit q (Gi2-mini-Gq chimera) / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 28.084832 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MGSTVSAEDK AAAERSKMID KNLREDGEKA RRTLRLLLLG ADNSGKSTIV KQMRILHGGS GGSGGTSGIF ETKFQVDKVN FHMFDVGGQ RDERRKWIQC FNDVTAIIFV VDSSDYNRLQ EALNDFKSIW NNRWLRTISV ILFLNKQDLL AEKVLAGKSK I EDYFPEFA ...String: MGSTVSAEDK AAAERSKMID KNLREDGEKA RRTLRLLLLG ADNSGKSTIV KQMRILHGGS GGSGGTSGIF ETKFQVDKVN FHMFDVGGQ RDERRKWIQC FNDVTAIIFV VDSSDYNRLQ EALNDFKSIW NNRWLRTISV ILFLNKQDLL AEKVLAGKSK I EDYFPEFA RYTTPEDATP EPGEDPRVTR AKYFIRKEFV DISTASGDGR HICYPHFTCA VDTENARRIF NDCKDIILQM NL REYNLV |
-Macromolecule #2: 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: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 37.41693 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL ...String: MSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL WDIETGQQTT TFTGHTGDVM SLSLAPDTRL FVSGACDASA KLWDVREGMC RQTFTGHESD INAICFFPNG NA FATGSDD ATCRLFDLRA DQELMTYSHD NIICGITSVS FSKSGRLLLA GYDDFNCNVW DALKADRAGV LAGHDNRVSC LGV TDDGMA VATGSWDSFL KIWN |
-Macromolecule #3: 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: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 7.861143 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L |
-Macromolecule #4: single-chain variable fragment 16 (scFv16)
Macromolecule | Name: single-chain variable fragment 16 (scFv16) / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 30.552234 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MLLVNQSHQG FNKEHTSKMV SAIVLYVLLA AAAHSAFADV QLVESGGGLV QPGGSRKLSC SASGFAFSSF GMHWVRQAPE KGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSEDT AMYYCVRSIY YYGSSPFDFW GQGTTLTVSS G GGGSGGGG ...String: MLLVNQSHQG FNKEHTSKMV SAIVLYVLLA AAAHSAFADV QLVESGGGLV QPGGSRKLSC SASGFAFSSF GMHWVRQAPE KGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSEDT AMYYCVRSIY YYGSSPFDFW GQGTTLTVSS G GGGSGGGG SGGGGSDIVM TQATSSVPVT PGESVSISCR SSKSLLHSNG NTYLYWFLQR PGQSPQLLIY RMSNLASGVP DR FSGSGSG TAFTLTISRL EAEDVGVYYC MQHLEYPLTF GAGTKLELK |
-Macromolecule #5: 5-hydroxytryptamine receptor 2B
Macromolecule | Name: 5-hydroxytryptamine receptor 2B / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 41.670207 KDa |
Recombinant expression | Organism: ![]() ![]() |
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 LQKKAYLVKN KPPQRLTWLT VSTVFQRDET PC SSPEKVA MLDGSRKDKA LPNSGDETLM RRTSTIGKKS VQTISNEQRA SKVLGIVFFL FLLMWCPFFI TNITLVLCDS CNQ TTLQML LEIFVWIGYV SSGVNPLVYT LFNKTFRDAF GRYITCNYRA TKSV |
-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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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Concentration | 8.5 mg/mL |
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Buffer | pH: 7.5 |
Grid | Model: UltrAuFoil R1.2/1.3 |
Vitrification | Cryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV |
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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: 1.07 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | C2 aperture diameter: 70.0 µm / Calibrated magnification: 55000 / 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 |