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- PDB-9wq6: 5-HT2AR bound to IHCH-1906 obtained by cryo-electron microscopy (... -

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Basic information

Entry
Database: PDB / ID: 9wq6
Title5-HT2AR bound to IHCH-1906 obtained by cryo-electron microscopy (cryoEM)
Components5-hydroxytryptamine receptor 2A
KeywordsSIGNALING PROTEIN/IMMUNE SYSTEM / GPCR / serotonin receptor / membrane protein / 5-HT2AR / SIGNALING PROTEIN-IMMUNE SYSTEM complex
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 / neurotransmitter receptor activity / negative regulation of synaptic transmission, glutamatergic / positive regulation of DNA biosynthetic process / temperature homeostasis / negative regulation of potassium ion transport / 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 / cytoplasmic vesicle / chemical synaptic transmission / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsLi, H. / Tang, L. / Zhang, J. / Meng, B. / Cao, D. / Chen, Y. / Yu, J. / Liu, Z. / Wang, S. / Cheng, J.
Funding support China, 1items
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 10, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Sep 16, 2026Provider: repository / Type: Initial release
Revision 1.0Sep 16, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.1Sep 30, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.1Sep 30, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
Data content type: EM metadata / EM metadata ...EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 5-hydroxytryptamine receptor 2A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,5182
Polymers38,2741
Non-polymers2431
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein 5-hydroxytryptamine receptor 2A / 5-HT-2 / 5-HT-2A / Serotonin receptor 2A


Mass: 38274.285 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HTR2A, HTR2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P28223
#2: Chemical ChemComp-A1EYE / 1-(1,2,3,6-tetrahydropyridin-4-yl)-6,7,8,9-tetrahydro-5~{H}-benzo[7]annulen-4-ol


Mass: 243.344 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C16H21NO / Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm) / Feature type: SUBJECT OF INVESTIGATION
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-HT2AR bound to IHCH-1906 obtained by cryo-electron microscopy (cryoEM)
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingAverage exposure time: 2 sec. / Electron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
2PHENIXmodel refinement
13PHENIX3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 251491 / Symmetry type: POINT
RefinementHighest resolution: 3.4 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0032019
ELECTRON MICROSCOPYf_angle_d0.5922761
ELECTRON MICROSCOPYf_dihedral_angle_d6.679292
ELECTRON MICROSCOPYf_chiral_restr0.037334
ELECTRON MICROSCOPYf_plane_restr0.005334

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