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- PDB-7srs: 5-HT2B receptor bound to LSD in complex with beta-arrestin1 obtai... -

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Basic information

Entry
Database: PDB / ID: 7srs
Title5-HT2B receptor bound to LSD in complex with beta-arrestin1 obtained by cryo-electron microscopy (cryoEM)
Components
  • (Anti-5HT2BR Fab ...) x 2
  • 5-hydroxytryptamine receptor 2B
  • Fab30 heavy chain
  • Fab30 light chain
  • Isoform 1B of Beta-arrestin-1
KeywordsMEMBRANE PROTEIN / 5-HT2B receptor / serotonin receptor / beta-arrestin1 / arrestin / GPCR / Lysergic acid diethylamide / LSD / cryoEM
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 / Golgi Associated Vesicle Biogenesis / negative regulation of NF-kappaB transcription factor activity ...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 / Golgi Associated Vesicle Biogenesis / negative regulation of NF-kappaB transcription factor activity / stress fiber assembly / negative regulation of Notch signaling pathway / 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 / G alpha (s) signalling events / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / transcription coactivator activity / positive regulation of ERK1 and ERK2 cascade / nuclear body / protein ubiquitination / Ub-specific processing proteases / positive regulation of protein phosphorylation / lysosomal membrane / Golgi 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
Arrestin, conserved site / Arrestins signature. / Arrestin / Arrestin, N-terminal / Arrestin-like, N-terminal / Arrestin C-terminal-like domain / Arrestin (or S-antigen), N-terminal domain / Arrestin (or S-antigen), C-terminal domain / Arrestin (or S-antigen), C-terminal domain / Arrestin-like, C-terminal / Immunoglobulin E-set
Similarity search - Domain/homology
Chem-7LD / Beta-arrestin-1
Similarity search - Component
Biological speciesMus musculus (house mouse)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsBarros-Alvarez, X. / Cao, C. / Panova, O. / Roth, B.L. / Skiniotis, G.
Funding support1items
OrganizationGrant numberCountry
Other government
CitationJournal: 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
DepositionNov 8, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 21, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 5, 2022Group: Structure summary / Category: chem_comp / Item: _chem_comp.pdbx_synonyms
Revision 1.2Oct 19, 2022Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.page_first

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
P: Anti-5HT2BR Fab light chain
Q: Anti-5HT2BR Fab heavy chain
R: 5-hydroxytryptamine receptor 2B
C: Isoform 1B of Beta-arrestin-1
H: Fab30 heavy chain
L: Fab30 light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)150,3838
Polymers149,8396
Non-polymers5452
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 2 types, 2 molecules RC

#3: Protein 5-hydroxytryptamine receptor 2B


Mass: 37722.496 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HTR2B / Production host: Spodoptera frugiperda (fall armyworm)
#4: Protein Isoform 1B of Beta-arrestin-1 / Arrestin beta-1 / Non-visual arrestin-2


Mass: 41345.305 Da / Num. of mol.: 1 / Mutation: R169E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ARRB1, ARR1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P49407

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Antibody , 4 types, 4 molecules PQHL

#1: Antibody Anti-5HT2BR Fab light chain


Mass: 22719.348 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm)
#2: Antibody Anti-5HT2BR Fab heavy chain


Mass: 23487.320 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm)
#5: Antibody Fab30 heavy chain


Mass: 13063.479 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm)
#6: Antibody Fab30 light chain


Mass: 11500.820 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm)

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Sugars / Non-polymers , 2 types, 2 molecules

#7: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#8: Chemical ChemComp-7LD / (8alpha)-N,N-diethyl-6-methyl-9,10-didehydroergoline-8-carboxamide / Lysergic acid diethylamide / Lysergic acid diethylamide


Mass: 323.432 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H25N3O / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: 5-HT2B receptor bound to LSD in complex with beta-arrestin1
Type: COMPLEX / Entity ID: #1-#6 / Source: MULTIPLE SOURCES
Molecular weightExperimental value: NO
Buffer solutionpH: 7.5
SpecimenConc.: 3.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Calibrated magnification: 57050 X / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 1.36 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
2SerialEMimage acquisition
4cryoSPARC3.2CTF correction
10cryoSPARC3.2initial Euler assignment
11cryoSPARC3.2final Euler assignment
13cryoSPARC3.23D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 4415425
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 126485 / Symmetry type: POINT

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