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- EMDB-68737: local refinement of 5HT2AR-miniGq heterotrimer in complex with a ... -

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Basic information

Entry
Database: EMDB / ID: EMD-68737
Titlelocal refinement of 5HT2AR-miniGq heterotrimer in complex with a selective agonist IHCH-2330
Map data
Sample
  • Complex: local refinement of 5-HT2A receptor bound to IHCH-2330 in complex with a mini-Gq protein and an active-state stabilizing single-chain variable fragment (scFv16) obtained by cryo-electron microscopy (cryoEM)
    • Protein or peptide: 5-hydroxytryptamine receptor 2A
  • Ligand: 3-[2-[2-[2,5-dimethoxy-4-(trifluoromethyl)phenyl]ethyl-methyl-amino]ethyl]-2-methyl-pyrido[1,2-a]pyrimidin-4-one
KeywordsGPCR / serotonin receptor / MEMBRANE PROTEIN / 5HT2AR
Function / homology
Function and homology information


positive regulation of heat generation / 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 / cell body fiber / artery smooth muscle contraction / positive regulation of cytokine production involved in immune response ...positive regulation of heat generation / 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 / cell body fiber / artery smooth muscle contraction / positive regulation of cytokine production involved in immune response / sensitization / Serotonin receptors / phospholipase C-activating serotonin receptor signaling pathway / G protein-coupled serotonin receptor activity / serotonin receptor signaling pathway / urinary bladder smooth muscle contraction / serotonin binding / positive regulation of platelet aggregation / negative regulation of synaptic transmission, glutamatergic / neurotransmitter receptor activity / positive regulation of DNA biosynthetic process / negative regulation of potassium ion transport / temperature homeostasis / detection of temperature stimulus involved in sensory perception of pain / regulation of dopamine secretion / detection of mechanical stimulus involved in sensory perception of pain / positive regulation of vasoconstriction / positive regulation of execution phase of apoptosis / protein tyrosine kinase activator activity / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / release of sequestered calcium ion into cytosol / behavioral response to cocaine / presynaptic modulation of chemical synaptic transmission / dendritic shaft / memory / caveola / intracellular calcium ion homeostasis / positive regulation of neuron apoptotic process / positive regulation of inflammatory response / presynapse / positive regulation of cytosolic calcium ion concentration / chemical synaptic transmission / cytoplasmic vesicle / presynaptic membrane / G alpha (q) signalling events / positive regulation of ERK1 and ERK2 cascade / postsynaptic membrane / 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. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile.
Similarity search - Domain/homology
5-hydroxytryptamine receptor 2A
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsTang L / Ji X / Cheng J / Wang S
Funding support China, 3 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
Chinese Academy of Sciences China
Ministry of Science and Technology (MoST, China) China
CitationJournal: Nat Commun / Year: 2026
Title: Mechanistic Basis for 5-HTR Over 5-HTR Activation.
Authors: Lingjie Tang / Xin Ji / Yumeng Wang / Dongmei Cao / Huiqiong Li / Licong He / Jianjun Cheng / Sheng Wang /
Abstract: Selective 5-HTR agonism without 5-HTR activation is critical for safe psychedelic-inspired therapeutics. Here, we systematically probe the ligand-binding pockets of 5-HTR and 5-HTR and identify ...Selective 5-HTR agonism without 5-HTR activation is critical for safe psychedelic-inspired therapeutics. Here, we systematically probe the ligand-binding pockets of 5-HTR and 5-HTR and identify steric and conformational constraints at the side-extended pocket (SEP) and extended binding pocket (EBP) that dictate ligand orientation and receptor signaling. Guided by these insights, we design derivatives across tryptamine and phenethylamine scaffolds that integrate SEP and EBP engagement with scaffold modification to reinforce 5-HTR activation while limiting 5-HTR activity. Cryo-EM structures of 5-HTR and 5-HTR bound to IHCH-2330, a selective 5-HTR agonist and 5-HTR antagonist, confirm the design principle. These findings show differential activation mechanisms between 5-HTR and 5-HTR and provide a rational framework for engineering safer, functionally selective serotonergic compounds, mitigating 5-HTR-mediated side effects while preserving therapeutic efficacy.
History
DepositionJan 26, 2026-
Header (metadata) releaseSep 16, 2026-
Map releaseSep 16, 2026-
UpdateSep 30, 2026-
Current statusSep 30, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_68737.png

Downloads & links

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Map

FileDownload / File: emd_68737.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
0.91 Å/pix.
x 256 pix.
= 232.96 Å		0.91 Å/pix.
x 256 pix.
= 232.96 Å		0.91 Å/pix.
x 256 pix.
= 232.96 Å

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.91 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.28
Minimum - Maximum-1.3768678 - 1.8173497
Average (Standard dev.)-0.00088753557 (±0.031115206)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 232.96 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_68737_half_map_1.map
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Half map: #2

Fileemd_68737_half_map_2.map
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Sample components

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Entire : local refinement of 5-HT2A receptor bound to IHCH-2330 in complex...

EntireName: local refinement of 5-HT2A receptor bound to IHCH-2330 in complex with a mini-Gq protein and an active-state stabilizing single-chain variable fragment (scFv16) obtained by cryo-electron microscopy (cryoEM)
Components
  • Complex: local refinement of 5-HT2A receptor bound to IHCH-2330 in complex with a mini-Gq protein and an active-state stabilizing single-chain variable fragment (scFv16) obtained by cryo-electron microscopy (cryoEM)
    • Protein or peptide: 5-hydroxytryptamine receptor 2A
  • Ligand: 3-[2-[2-[2,5-dimethoxy-4-(trifluoromethyl)phenyl]ethyl-methyl-amino]ethyl]-2-methyl-pyrido[1,2-a]pyrimidin-4-one

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Supramolecule #1: local refinement of 5-HT2A receptor bound to IHCH-2330 in complex...

SupramoleculeName: local refinement of 5-HT2A receptor bound to IHCH-2330 in complex with a mini-Gq protein and an active-state stabilizing single-chain variable fragment (scFv16) obtained by cryo-electron microscopy (cryoEM)
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: 37.50727 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GPGSGSGLSL LHLQEKNWSA LLTAVVIILT IAGNILVIMA VSLEKKLQNA TNYFLMSLAI ADMLLGFLVM PVSMLTILYG YRWPLPSKL CAVWIYLDVL FSTASIMHLC AISLDRYVAI QNPIHHSRFN SRTKAFLKII AVWTISVGIS MPIPVFGLQD D SKVFKEGS ...String:
GPGSGSGLSL LHLQEKNWSA LLTAVVIILT IAGNILVIMA VSLEKKLQNA TNYFLMSLAI ADMLLGFLVM PVSMLTILYG YRWPLPSKL CAVWIYLDVL FSTASIMHLC AISLDRYVAI QNPIHHSRFN SRTKAFLKII AVWTISVGIS MPIPVFGLQD D SKVFKEGS CLLADDNFVL IGSFVSFFIP LTIMVITYFL TIKSLQKEAT LCVSDLGTRA KLASFSFLPQ SSLSSEKLFQ RS IHREPGS YTGRRTMQSI SNEQKACKVL GIVFFLFVVM WCPFFITNIM AVICKESCNE DVIGALLNVF VWIGYLSSAV NPL VYTLFN KTYRSAFSRY

UniProtKB: 5-hydroxytryptamine receptor 2A

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Macromolecule #2: 3-[2-[2-[2,5-dimethoxy-4-(trifluoromethyl)phenyl]ethyl-methyl-ami...

MacromoleculeName: 3-[2-[2-[2,5-dimethoxy-4-(trifluoromethyl)phenyl]ethyl-methyl-amino]ethyl]-2-methyl-pyrido[1,2-a]pyrimidin-4-one
type: ligand / ID: 2 / Number of copies: 1 / Formula: A1EXY
Molecular weightTheoretical: 449.466 Da

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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
GridModel: Quantifoil / Material: GOLD / Mesh: 300
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average exposure time: 2.0 sec. / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7ran

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: CCP4 package / Number images used: 186920
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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