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Yorodumi- 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) | |||||||||
Map data | Composite cryo-EM map for 5-HT2BR bound to LSD in complex with heterotrimeric mini-Gq | |||||||||
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Keywords | 5-HT2B receptor / serotonin receptor / G protein / GPCR / Lysergic acid diethylamide / LSD / cryoEM / MEMBRANE PROTEIN | |||||||||
| Function / homology | Function and homology informationintestine smooth muscle contraction / Gq/11-coupled serotonin receptor activity / positive regulation of phosphatidylinositol biosynthetic process / G protein-coupled serotonin receptor signaling pathway / G protein-coupled serotonin receptor complex / regulation of behavior / phospholipase C-activating serotonin receptor signaling pathway / Serotonin receptors / serotonin receptor activity / G protein-coupled serotonin receptor activity ...intestine smooth muscle contraction / Gq/11-coupled serotonin receptor activity / positive regulation of phosphatidylinositol biosynthetic process / G protein-coupled serotonin receptor signaling pathway / G protein-coupled serotonin receptor complex / regulation of behavior / phospholipase C-activating serotonin receptor signaling pathway / Serotonin receptors / serotonin receptor activity / G protein-coupled serotonin receptor activity / embryonic morphogenesis / serotonin receptor signaling pathway / vasoconstriction / neurotransmitter receptor activity / serotonin binding / cardiac muscle hypertrophy / neural crest cell migration / : / neural crest cell differentiation / positive regulation of cell division / G-protein alpha-subunit binding / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / heart morphogenesis / ERK1 and ERK2 cascade / positive regulation of endothelial cell proliferation / release of sequestered calcium ion into cytosol / GTPase activator activity / positive regulation of cytokine production / calcium-mediated signaling / Olfactory Signaling Pathway / Activation of the phototransduction cascade / intracellular calcium ion homeostasis / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / photoreceptor disc membrane / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / ADP signalling through P2Y purinoceptor 1 / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / cellular response to prostaglandin E stimulus / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / sensory perception of taste / Thrombin signalling through proteinase activated receptors (PARs) / signaling receptor complex adaptor activity / retina development in camera-type eye / GTPase binding / Ca2+ pathway / fibroblast proliferation / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / chemical synaptic transmission / Ras protein signal transduction / Extra-nuclear estrogen signaling / positive regulation of ERK1 and ERK2 cascade / cell population proliferation / positive regulation of canonical NF-kappaB signal transduction / G protein-coupled receptor signaling pathway / response to xenobiotic stimulus / lysosomal membrane / GTPase activity / positive regulation of cell population proliferation / synapse / dendrite / negative regulation of apoptotic process / protein-containing complex binding / signal transduction / extracellular exosome / nucleoplasm / membrane / plasma membrane / cytosol / cytoplasm Similarity search - Function | |||||||||
| Biological species | Homo sapiens (human) | |||||||||
| Method | single particle reconstruction / cryo EM / Resolution: 2.9 Å | |||||||||
Authors | Barros-Alvarez X / Kim K | |||||||||
| Funding support | 1 items
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Citation | Journal: Neuron / Year: 2022Title: 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. | |||||||||
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Structure visualization
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Downloads & links
-EMDB archive
| Map data | emd_25402.map.gz | 1.5 MB | EMDB map data format | |
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| Header (meta data) | emd-25402-v30.xml emd-25402.xml | 25.5 KB 25.5 KB | Display Display | EMDB header |
| Images | emd_25402.png | 103.8 KB | ||
| Filedesc metadata | emd-25402.cif.gz | 7.4 KB | ||
| Others | emd_25402_additional_1.map.gz emd_25402_additional_2.map.gz | 744.2 KB 1.8 MB | ||
| Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-25402 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-25402 | HTTPS FTP |
-Validation report
| Summary document | emd_25402_validation.pdf.gz | 330.4 KB | Display | EMDB validaton report |
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| Full document | emd_25402_full_validation.pdf.gz | 330 KB | Display | |
| Data in XML | emd_25402_validation.xml.gz | 6.7 KB | Display | |
| Data in CIF | emd_25402_validation.cif.gz | 7.9 KB | Display | |
| Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-25402 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-25402 | 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 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_25402.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 heterotrimeric mini-Gq | ||||||||||||||||||||||||||||||||||||
| Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
| 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: Homo sapiens (human) |
-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: Homo sapiens (human) |
| 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: Homo sapiens (human) |
| 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 UniProtKB: 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 | 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: 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 #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: Homo sapiens (human) |
| 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: Homo sapiens (human) |
| 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 UniProtKB: 5-hydroxytryptamine receptor 2B |
-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
| 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: FIELD EMISSION GUN |
| 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 |
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Keywords
Homo sapiens (human)
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Processing
FIELD EMISSION GUN
