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- EMDB-43797: Local refinement of 5-HT2AR bound to 5-HT in complex with a mini-... -

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Basic information

Entry
Database: EMDB / ID: EMD-43797
TitleLocal refinement of 5-HT2AR bound to 5-HT in complex with a mini-Gq protein and scFv16 obtained by cryo-electron microscopy (cryoEM)
Map data
Sample
  • Complex: 5-HT2AR in complex with mini-Gq
    • Protein or peptide: 5-hydroxytryptamine receptor 2A
  • Ligand: SEROTONIN
KeywordsGPCR / G-protein Coupled Receptor / 5-HT2AR / serotonin / psychedelics / MEMBRANE PROTEIN
Function / homology
Function and homology information


positive regulation of heat generation / protein localization to cytoskeleton / 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine binding / 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 / neurofilament / Serotonin receptors / serotonin receptor activity ...positive regulation of heat generation / protein localization to cytoskeleton / 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine binding / 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 / neurofilament / Serotonin receptors / serotonin receptor activity / cell body fiber / phospholipase C-activating serotonin receptor signaling pathway / positive regulation of cytokine production involved in immune response / G protein-coupled serotonin receptor activity / artery smooth muscle contraction / serotonin receptor signaling pathway / sensitization / urinary bladder smooth muscle contraction / serotonin binding / negative regulation of synaptic transmission, glutamatergic / positive regulation of platelet aggregation / positive regulation of DNA biosynthetic process / neurotransmitter receptor activity / temperature homeostasis / regulation of dopamine secretion / negative regulation of potassium ion transport / behavioral response to cocaine / detection of temperature stimulus involved in sensory perception of pain / protein tyrosine kinase activator activity / positive regulation of execution phase of apoptosis / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / positive regulation of fat cell differentiation / detection of mechanical stimulus involved in sensory perception of pain / positive regulation of vasoconstriction / release of sequestered calcium ion into cytosol / presynaptic modulation of chemical synaptic transmission / dendritic shaft / positive regulation of glycolytic process / glycolytic process / caveola / memory / intracellular calcium ion homeostasis / positive regulation of inflammatory response / positive regulation of peptidyl-tyrosine phosphorylation / positive regulation of neuron apoptotic process / presynaptic membrane / virus receptor activity / positive regulation of cytosolic calcium ion concentration / cytoplasmic vesicle / chemical synaptic transmission / G alpha (q) signalling events / postsynaptic membrane / positive regulation of ERK1 and ERK2 cascade / response to xenobiotic stimulus / axon / neuronal cell body / positive regulation of cell population proliferation / dendrite / protein-containing complex binding / glutamatergic synapse / identical protein binding / plasma membrane
Similarity search - Function
5-Hydroxytryptamine 2A receptor / 5-hydroxytryptamine receptor family / Serpentine type 7TM GPCR chemoreceptor Srsx / 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)
Similarity search - Domain/homology
5-hydroxytryptamine receptor 2A
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.24 Å
AuthorsGumpper RH / Fay JF / Roth BL
Funding support United States, 1 items
OrganizationGrant numberCountry
Defense Advanced Research Projects Agency (DARPA)HR0011-20-2-0029 United States
CitationJournal: Nat Commun / Year: 2025
Title: The structural diversity of psychedelic drug actions revealed.
Authors: Ryan H Gumpper / Manish K Jain / Kuglae Kim / Renhong Sun / Ning Sun / Zhongli Xu / Jeffrey F DiBerto / Brian E Krumm / Nicholas J Kapolka / H Ümit Kaniskan / David E Nichols / Jian Jin / ...Authors: Ryan H Gumpper / Manish K Jain / Kuglae Kim / Renhong Sun / Ning Sun / Zhongli Xu / Jeffrey F DiBerto / Brian E Krumm / Nicholas J Kapolka / H Ümit Kaniskan / David E Nichols / Jian Jin / Jonathan F Fay / Bryan L Roth /
Abstract: There is currently a resurgence in exploring the utility of classical psychedelics to treat depression, addiction, anxiety disorders, cluster headaches, and many other neuropsychiatric disorders. A ...There is currently a resurgence in exploring the utility of classical psychedelics to treat depression, addiction, anxiety disorders, cluster headaches, and many other neuropsychiatric disorders. A biological target of these compounds, and a hypothesized target for their therapeutic actions, is the 5-HT serotonin receptor. Here, we present 7 cryo-EM structures covering all major compound classes of psychedelic and non-psychedelic agonists, including a β-arrestin-biased compound RS130-180. Identifying the molecular interactions between various psychedelics and the 5-HT receptor reveals both common and distinct motifs among the examined psychedelic chemotypes. These findings lead to a broader mechanistic understanding of 5-HT activation, which can catalyze the development of novel chemotypes with potential therapeutic utility and fewer side effects.
History
DepositionFeb 24, 2024-
Header (metadata) releaseApr 2, 2025-
Map releaseApr 2, 2025-
UpdateApr 2, 2025-
Current statusApr 2, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43797.png

Downloads & links

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Map

FileDownload / File: emd_43797.map.gz / Format: CCP4 / Size: 115.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
0.88 Å/pix.
x 312 pix.
= 274.56 Å		0.88 Å/pix.
x 312 pix.
= 274.56 Å		0.88 Å/pix.
x 312 pix.
= 274.56 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.88 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.169
Minimum - Maximum-1.041727 - 1.4159186
Average (Standard dev.)-0.0004420024 (±0.018342892)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions312312312
Spacing312312312
CellA=B=C: 274.56 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_43797_msk_1.map
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Half map: #2

Fileemd_43797_half_map_1.map
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Half map: #1

Fileemd_43797_half_map_2.map
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Sample components

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Entire : 5-HT2AR in complex with mini-Gq

EntireName: 5-HT2AR in complex with mini-Gq
Components
  • Complex: 5-HT2AR in complex with mini-Gq
    • Protein or peptide: 5-hydroxytryptamine receptor 2A
  • Ligand: SEROTONIN

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Supramolecule #1: 5-HT2AR in complex with mini-Gq

SupramoleculeName: 5-HT2AR in complex with mini-Gq / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: 5-hydroxytryptamine receptor 2A

MacromoleculeName: 5-hydroxytryptamine receptor 2A / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 52.648945 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MDILCEENTS LSSTTNSLMQ LNDDTRLYSN DFNSGEANTS DAFNWTVDSE NRTNLSCEGC LSPSCLSLLH LQEKNWSALL TAVVIILTI AGNILVIMAV SLEKKLQNAT NYFLMSLAIA DMLLGFLVMP VSMLTILYGY RWPLPSKLCA VWIYLDVLFS T ASIMHLCA ...String:
MDILCEENTS LSSTTNSLMQ LNDDTRLYSN DFNSGEANTS DAFNWTVDSE NRTNLSCEGC LSPSCLSLLH LQEKNWSALL TAVVIILTI AGNILVIMAV SLEKKLQNAT NYFLMSLAIA DMLLGFLVMP VSMLTILYGY RWPLPSKLCA VWIYLDVLFS T ASIMHLCA ISLDRYVAIQ NPIHHSRFNS RTKAFLKIIA VWTISVGISM PIPVFGLQDD SKVFKEGSCL LADDNFVLIG SF VSFFIPL TIMVITYFLT IKSLQKEATL CVSDLGTRAK LASFSFLPQS SLSSEKLFQR SIHREPGSYT GRRTMQSISN EQK ACKVLG IVFFLFVVMW CPFFITNIMA VICKESCNED VIGALLNVFV WIGYLSSAVN PLVYTLFNKT YRSAFSRYIQ CQYK ENKKP LQLILVNTIP ALAYKSSQLQ MGQKKNSKQD AKTTDNDCSM VALGKQHSEE ASKDNSDGVN EKVSCV

UniProtKB: 5-hydroxytryptamine receptor 2A

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Macromolecule #2: SEROTONIN

MacromoleculeName: SEROTONIN / type: ligand / ID: 2 / Number of copies: 1 / Formula: SRO
Molecular weightTheoretical: 176.215 Da
Chemical component information

ChemComp-SRO:
SEROTONIN / neurotransmitter*YM

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 49.5 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: OTHER / Nominal defocus max: 2.6 µm / Nominal defocus min: 0.16 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7ran

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.24 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 157415
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: ANGULAR RECONSTITUTION

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