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- PDB-7srr: 5-HT2B receptor bound to LSD in complex with heterotrimeric mini-... -

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Basic information

Entry
Database: PDB / ID: 7srr
Title5-HT2B receptor bound to LSD in complex with heterotrimeric mini-Gq protein obtained by cryo-electron microscopy (cryoEM)
Components
  • (Guanine nucleotide-binding protein ...) x 2
  • 5-hydroxytryptamine receptor 2B
  • G protein subunit q (Gi2-mini-Gq chimera)
  • single-chain variable fragment 16 (scFv16)
KeywordsMEMBRANE PROTEIN / 5-HT2B receptor / serotonin receptor / G protein / GPCR / Lysergic acid diethylamide / LSD / cryoEM
Function / homology
Function and homology information


intestine smooth muscle contraction / Gq/11-coupled serotonin receptor activity / positive regulation of phosphatidylinositol biosynthetic process / G protein-coupled serotonin receptor signaling pathway / regulation of behavior / G protein-coupled serotonin receptor complex / Serotonin receptors / serotonin receptor activity / phospholipase C-activating serotonin receptor signaling pathway / 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 / regulation of behavior / G protein-coupled serotonin receptor complex / Serotonin receptors / serotonin receptor activity / phospholipase C-activating serotonin receptor signaling pathway / G protein-coupled serotonin receptor activity / serotonin receptor signaling pathway / embryonic morphogenesis / serotonin binding / vasoconstriction / cardiac muscle hypertrophy / neural crest cell migration / neural crest cell differentiation / cGMP-mediated signaling / neurotransmitter receptor activity / positive regulation of cell division / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / 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 / positive regulation of cytokine production / calcium-mediated signaling / 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-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / intracellular calcium ion homeostasis / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / 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 / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / Ca2+ pathway / retina development in camera-type eye / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / fibroblast proliferation / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / G alpha (s) signalling events / chemical synaptic transmission / G alpha (q) signalling events / positive regulation of canonical NF-kappaB signal transduction / Ras protein signal transduction / positive regulation of ERK1 and ERK2 cascade / Extra-nuclear estrogen signaling / cell population proliferation / G protein-coupled receptor signaling pathway / response to xenobiotic stimulus / lysosomal membrane / GTPase activity / positive regulation of cell population proliferation / dendrite / synapse / protein-containing complex binding / negative regulation of apoptotic process / signal transduction / extracellular exosome / nucleoplasm / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
5-Hydroxytryptamine 2B receptor / 5-hydroxytryptamine receptor family / YVTN repeat-like/Quinoprotein amine dehydrogenase / Serpentine type 7TM GPCR chemoreceptor Srsx / 7 Propeller / Methylamine Dehydrogenase; Chain H / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily ...5-Hydroxytryptamine 2B receptor / 5-hydroxytryptamine receptor family / YVTN repeat-like/Quinoprotein amine dehydrogenase / Serpentine type 7TM GPCR chemoreceptor Srsx / 7 Propeller / Methylamine Dehydrogenase; Chain H / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / P-loop containing nucleotide triphosphate hydrolases / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Rossmann fold / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Chem-7LD / 5-hydroxytryptamine receptor 2B / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsBarros-Alvarez, X. / Kim, K. / Panova, O. / Cao, C. / 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
Revision 1.3Nov 20, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: G protein subunit q (Gi2-mini-Gq chimera)
C: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
D: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
E: single-chain variable fragment 16 (scFv16)
R: 5-hydroxytryptamine receptor 2B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)145,9096
Polymers145,5855
Non-polymers3231
Water00
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 BR

#1: Protein G protein subunit q (Gi2-mini-Gq chimera)


Mass: 28084.832 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)
#5: Protein 5-hydroxytryptamine receptor 2B / 5-HT-2B / 5-HT2B / Serotonin receptor 2B


Mass: 41670.207 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) / References: UniProt: P41595

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Guanine nucleotide-binding protein ... , 2 types, 2 molecules CD

#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37416.930 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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Antibody / Non-polymers , 2 types, 2 molecules E

#4: Antibody single-chain variable fragment 16 (scFv16)


Mass: 30552.234 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)
#6: Chemical ChemComp-7LD / (8alpha)-N,N-diethyl-6-methyl-9,10-didehydroergoline-8-carboxamide / 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
Has protein modificationY

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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 heterotrimeric mini-Gq protein and single-chain variable fragment (scFv16)
Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenConc.: 8.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid type: UltrAuFoil R1.2/1.3
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 FIELD / Calibrated magnification: 55000 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: 1.07 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
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: 3214021
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 772614 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0038570
ELECTRON MICROSCOPYf_angle_d0.53711679
ELECTRON MICROSCOPYf_dihedral_angle_d3.9841193
ELECTRON MICROSCOPYf_chiral_restr0.0421376
ELECTRON MICROSCOPYf_plane_restr0.0031465

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