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- EMDB-66165: 5-HT2B receptor bound to IHCH-6122 in complex with an antibody ob... -

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Basic information

Entry
Database: EMDB / ID: EMD-66165
Title5-HT2B receptor bound to IHCH-6122 in complex with an antibody obtained by cryo-electron microscopy (cryoEM)
Map data
Sample
  • Complex: 5-HT2B receptor bound to IHCH-6122 in complex with an antibody obtained by cryo-electron microscopy (cryoEM)
    • Protein or peptide: 5-hydroxytryptamine receptor 2B
    • Protein or peptide: Anti-5-HT2B Fab light chain
    • Protein or peptide: Anti-5-HT2B Fab heavy chain
  • Ligand: 3-piperazin-1-yl-5,6,7,8-tetrahydroisoquinoline
KeywordsGPCR / serotonin receptor / membrane protein / 5-HT2AR / SIGNALING PROTEIN/IMMUNE SYSTEM / SIGNALING PROTEIN-IMMUNE SYSTEM complex
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 / G protein-coupled serotonin receptor complex / regulation of behavior / vasoconstriction / embryonic morphogenesis / Serotonin receptors / phospholipase C-activating serotonin receptor signaling pathway ...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 / vasoconstriction / embryonic morphogenesis / Serotonin receptors / phospholipase C-activating serotonin receptor signaling pathway / G protein-coupled serotonin receptor activity / serotonin receptor signaling pathway / neural crest cell migration / cardiac muscle hypertrophy / serotonin binding / neural crest cell differentiation / positive regulation of cell division / neurotransmitter receptor activity / ERK1 and ERK2 cascade / heart morphogenesis / G-protein alpha-subunit binding / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / release of sequestered calcium ion into cytosol / positive regulation of endothelial cell proliferation / GTPase activator activity / positive regulation of cytokine production / calcium-mediated signaling / intracellular calcium ion homeostasis / chemical synaptic transmission / G alpha (q) signalling events / positive regulation of ERK1 and ERK2 cascade / positive regulation of canonical NF-kappaB signal transduction / response to xenobiotic stimulus / G protein-coupled receptor signaling pathway / positive regulation of cell population proliferation / negative regulation of apoptotic process / dendrite / synapse / nucleoplasm / plasma membrane / cytoplasm
Similarity search - Function
5-Hydroxytryptamine 2B 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 2B
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.18 Å
AuthorsLi H / Tang L / Zhang J / Meng B / Cao D / Yu J / Liu Z / Wang S / Cheng J
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Commun / Year: 2026
Title: Structure-based design of subtype-selective psychedelic analogs.
Authors: Huiqiong Li / Lingjie Tang / Jinfeng Zhang / Bing Meng / Dongmei Cao / Yujin Chen / Jing Yu / Huan Wang / Zhi-Jie Liu / Sheng Wang / Jianjun Cheng /
Abstract: Classical psychedelics exert hallucinogenic and therapeutic effects primarily through activation of serotonin 2 A receptor (5-HTR), offering promise as transformative treatments for ...Classical psychedelics exert hallucinogenic and therapeutic effects primarily through activation of serotonin 2 A receptor (5-HTR), offering promise as transformative treatments for neuropsychiatric disorders. However, their concurrent activation of 5-HTR-associated with cardiac valvulopathy-raises serious safety concerns, underscoring the need for subtype-selective psychedelics. To address this, we determine the cryo-EM structure of 5-HTR and perform a comparative structural analysis of the orthosteric binding pockets (OBPs) of 5-HTR and 5-HTR. Guided by key residue differences, we develop a trigonal pharmacophore model to inform the design of 5-HTR-selective agonists that avoid 5-HTR activation. Using this model, we design and synthesize two compound series that selectively activate 5-HTR while antagonizing 5-HTR. Molecular basis of subtype selectivity is confirmed by five additional cryo-EM structures of receptor-ligand complexes. Selected compounds also exhibit antidepressant-like efficacy in animal models. Our findings provide a strategy for the development of safer, subtype-selective psychedelic analogs with therapeutic potential.
History
DepositionSep 11, 2025-
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_66165.png

Downloads & links

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Map

FileDownload / File: emd_66165.map.gz / Format: CCP4 / Size: 67 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
1.15 Å/pix.
x 260 pix.
= 299. Å		1.15 Å/pix.
x 260 pix.
= 299. Å		1.15 Å/pix.
x 260 pix.
= 299. Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.15 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.23
Minimum - Maximum-1.8139906 - 3.0117886
Average (Standard dev.)-0.00017758313 (±0.035629377)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions260260260
Spacing260260260
CellA=B=C: 299.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_66165_half_map_1.map
Projections & Slices
AxesZYX

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Half map: #2

Fileemd_66165_half_map_2.map
Projections & Slices
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Sample components

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Entire : 5-HT2B receptor bound to IHCH-6122 in complex with an antibody ob...

EntireName: 5-HT2B receptor bound to IHCH-6122 in complex with an antibody obtained by cryo-electron microscopy (cryoEM)
Components
  • Complex: 5-HT2B receptor bound to IHCH-6122 in complex with an antibody obtained by cryo-electron microscopy (cryoEM)
    • Protein or peptide: 5-hydroxytryptamine receptor 2B
    • Protein or peptide: Anti-5-HT2B Fab light chain
    • Protein or peptide: Anti-5-HT2B Fab heavy chain
  • Ligand: 3-piperazin-1-yl-5,6,7,8-tetrahydroisoquinoline

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Supramolecule #1: 5-HT2B receptor bound to IHCH-6122 in complex with an antibody ob...

SupramoleculeName: 5-HT2B receptor bound to IHCH-6122 in complex with an antibody obtained by cryo-electron microscopy (cryoEM)
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: 5-hydroxytryptamine receptor 2B

MacromoleculeName: 5-hydroxytryptamine receptor 2B / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 35.582152 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GPGSGSGTES IPEEMKQIVE EQGNKLHWAA LLILMVIIPT IGGNTLVILA VSLEKKLQYA TNYFLMSLAV ADLLVGLFVM PIALLTIMF EAMWPLPLVL CPAWLFLDVL FSTASIWHLC AISVDRYIAI KKPIQANQYN SRATAFIKIT VVWLISIGIA I PVPIKGIE ...String:
GPGSGSGTES IPEEMKQIVE EQGNKLHWAA LLILMVIIPT IGGNTLVILA VSLEKKLQYA TNYFLMSLAV ADLLVGLFVM PIALLTIMF EAMWPLPLVL CPAWLFLDVL FSTASIWHLC AISVDRYIAI KKPIQANQYN SRATAFIKIT VVWLISIGIA I PVPIKGIE TDVDNPNNIT CVLTKERFGD FMLFGSLAAF FTPLAIMIVT YFLTIHALQK KRLLSGSRQT ISNEQRASKV LG IVFFLFL LMWCPFFITN ITLVLCDSCN QTTLQMLLEI FVWIGYVSSG VNPLVYTLFN KTFRDAFGRY ITCNYRATKS V

UniProtKB: 5-hydroxytryptamine receptor 2B

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Macromolecule #2: Anti-5-HT2B Fab light chain

MacromoleculeName: Anti-5-HT2B Fab light chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.151842 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: DIVLIQSPAI MSASPGEKVT ITCSASSSVS YMHWFQQKPG TSPKLWIYST SNLASGVPAR FSGSGSGTSY SLTISRMEAE DAATYYCQQ RSSYPLTFGA GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ E SVTEQDSK ...String:
DIVLIQSPAI MSASPGEKVT ITCSASSSVS YMHWFQQKPG TSPKLWIYST SNLASGVPAR FSGSGSGTSY SLTISRMEAE DAATYYCQQ RSSYPLTFGA GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ E SVTEQDSK DSTYSLSSTL TLSKADYEKH KVYACEVTHQ GLSLPVTKSF NRGEC

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Macromolecule #3: Anti-5-HT2B Fab heavy chain

MacromoleculeName: Anti-5-HT2B Fab heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 26.785811 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: EVQLQQSGPE LVKPGASVKL SCKASGYTFT SSWMHWVKQR PGQGLEWIGN IYPSNGGTNY NERFKSKATL TVDRSSNTAY MQLSSLTSE DSAVYFCARF GSFITTILTT YYNPVDYWGQ GTTLTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY F PEPVTVSW ...String:
EVQLQQSGPE LVKPGASVKL SCKASGYTFT SSWMHWVKQR PGQGLEWIGN IYPSNGGTNY NERFKSKATL TVDRSSNTAY MQLSSLTSE DSAVYFCARF GSFITTILTT YYNPVDYWGQ GTTLTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY F PEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY ICNVNHKPSN TKVDKKVEPK SCENLYFQSG SH HHHHHHH

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Macromolecule #4: 3-piperazin-1-yl-5,6,7,8-tetrahydroisoquinoline

MacromoleculeName: 3-piperazin-1-yl-5,6,7,8-tetrahydroisoquinoline / type: ligand / ID: 4 / Number of copies: 1 / Formula: A1EYD
Molecular weightTheoretical: 217.31 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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number real images: 8245 / 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:

8uwl

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.18 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: PHENIX / Number images used: 615596
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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