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- PDB-9ll9: DOI-bound Serotonin 2A (5-HT2A) receptor-Gq complex -

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Basic information

Entry
Database: PDB / ID: 9ll9
TitleDOI-bound Serotonin 2A (5-HT2A) receptor-Gq complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • 5-hydroxytryptamine receptor 2A
KeywordsMEMBRANE PROTEIN / complex / agonist
Function / homology
Function and homology information


protein localization to cytoskeleton / sensory perception of itch / 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 / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion ...protein localization to cytoskeleton / sensory perception of itch / 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 / Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / phospholipase C-activating G protein-coupled glutamate receptor signaling pathway / cell body fiber / PLC beta mediated events / phospholipase C-activating serotonin receptor signaling pathway / artery smooth muscle contraction / positive regulation of cytokine production involved in immune response / serotonin receptor activity / Serotonin receptors / regulation of platelet activation / entrainment of circadian clock / G protein-coupled serotonin receptor activity / serotonin receptor signaling pathway / sensitization / neurotransmitter receptor activity / urinary bladder smooth muscle contraction / serotonin binding / positive regulation of platelet aggregation / regulation of canonical Wnt signaling pathway / negative regulation of synaptic transmission, glutamatergic / cellular response to acidic pH / positive regulation of DNA biosynthetic process / glutamate receptor signaling pathway / mast cell degranulation / temperature homeostasis / detection of temperature stimulus involved in sensory perception of pain / regulation of dopamine secretion / negative regulation of potassium ion transport / protein tyrosine kinase activator activity / positive regulation of vasoconstriction / phototransduction, visible light / PKA activation in glucagon signalling / developmental growth / hair follicle placode formation / positive regulation of execution phase of apoptosis / photoreceptor outer segment / intracellular transport / detection of mechanical stimulus involved in sensory perception of pain / D1 dopamine receptor binding / positive regulation of fat cell differentiation / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / postsynaptic cytosol / vascular endothelial cell response to laminar fluid shear stress / renal water homeostasis / Hedgehog 'off' state / activation of adenylate cyclase activity / adenylate cyclase inhibitor activity / adenylate cyclase-activating adrenergic receptor signaling pathway / positive regulation of protein localization to cell cortex / behavioral response to cocaine / T cell migration / positive regulation of relaxation of smooth muscle / Adenylate cyclase inhibitory pathway / response to prostaglandin E / release of sequestered calcium ion into cytosol / hormone-mediated signaling pathway / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / regulation of insulin secretion / adenylate cyclase-inhibiting serotonin receptor signaling pathway / cellular response to glucagon stimulus / presynaptic modulation of chemical synaptic transmission / cellular response to forskolin / GTPase activator activity / chemokine-mediated signaling pathway / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / positive regulation of glycolytic process / regulation of mitotic spindle organization / dendritic shaft / adenylate cyclase activator activity / trans-Golgi network membrane / glycolytic process / neuropeptide signaling pathway / negative regulation of inflammatory response to antigenic stimulus / Regulation of insulin secretion / positive regulation of cholesterol biosynthetic process / negative regulation of insulin secretion / G protein-coupled receptor binding / bone development / caveola / response to peptide hormone / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / platelet aggregation / cognition / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / centriolar satellite / memory / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / intracellular calcium ion homeostasis
Similarity search - Function
5-Hydroxytryptamine 2A receptor / G-protein alpha subunit, group Q / 5-hydroxytryptamine receptor family / G-protein alpha subunit, group S / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. ...5-Hydroxytryptamine 2A receptor / G-protein alpha subunit, group Q / 5-hydroxytryptamine receptor family / G-protein alpha subunit, group S / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / 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 / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / 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. / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
: / CHOLESTEROL / 5-hydroxytryptamine receptor 2A / Guanine nucleotide-binding protein G(q) subunit alpha / 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 / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Guanine nucleotide-binding protein G(i) subunit alpha-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.76 Å
AuthorsXu, Z. / Shao, Z.H.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82404716 China
CitationJournal: Nature / Year: 2026
Title: Psychedelics elicit their effects by 5-HT receptor-mediated G signalling.
Authors: Zheng Xu / Hongshuang Wang / Jingjing Yu / Yue Deng / Xiaowen Tian / Rongjun Ni / Fan Xia / Lingyi Yang / Chanjuan Xu / Liting Zhang / Renxuan Luo / Peipei Chen / Xiaoyu Zhang / Yuxuan Liu / ...Authors: Zheng Xu / Hongshuang Wang / Jingjing Yu / Yue Deng / Xiaowen Tian / Rongjun Ni / Fan Xia / Lingyi Yang / Chanjuan Xu / Liting Zhang / Renxuan Luo / Peipei Chen / Xiaoyu Zhang / Yuxuan Liu / Jingyu Hou / Miyuan Zhang / Shasha Chen / Lantian Su / Hui Sun / Yixiao He / Dandan Chen / Xiaoting Chen / Zhuang Miao / Jie Xie / Xinlei Liu / Jie Zhao / Bowen Ke / Xiaohe Tian / Linan Zeng / Lingli Zhang / Xiangdong Tang / Shengyong Yang / Jianfeng Liu / Xiaohui Wang / Wei Yan / Zhenhua Shao /
Abstract: Psychedelics are undergoing a renaissance as potential therapy for psychiatric disorders, with more than 200 clinical trials being studied across several countries. However, the precise mechanisms by ...Psychedelics are undergoing a renaissance as potential therapy for psychiatric disorders, with more than 200 clinical trials being studied across several countries. However, the precise mechanisms by which these drugs bring about benefits and the potential clinical risks are not yet fully understood. The serotonin 2A receptor (5-HTR) was reported to be a G-coupled receptor and the primary interoceptive target of psychedelics. Here we compared psychedelics and their non-hallucinogenic analogues (nHAs) using in vitro and in vivo approaches, finding that 5-HTR-mediated non-canonical G signalling is essential for hallucinogenic effect. We further presented five cryo-electron microscopy structures of 5-HTR-G/G in complex with psychedelics or nHAs. Structural analysis and pharmacological investigation revealed that a special contact between nHAs with 5-HTR mediated the signalling bias. Building on this insight, we identified a 2,5-dimethoxy-4-iodoamphetamine derivative, DOI-NBOMe, which exhibits potent and selective G-biased activity, and demonstrates promising therapeutic effects in mouse models without hallucinogenic effect. Our finding uncovers the functional mechanisms underlying the G signalling mediated by 5-HTR and provides valuable insights for designing psychedelic-based drugs with minimized risk from hallucinogenic effects.
History
DepositionJan 17, 2025Deposition site: PDBJ / Processing site: PDBC
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
C: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
A: Guanine nucleotide-binding protein G(i) subunit alpha-1,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short,Guanine nucleotide-binding protein G(q) subunit alpha
R: 5-hydroxytryptamine receptor 2A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)140,2996
Polymers139,5914
Non-polymers7082
Water23413
1


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

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules BCA

#1: 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
#2: 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
#3: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short,Guanine nucleotide-binding protein G(q) subunit alpha / Adenylate cyclase-inhibiting G alpha protein / Adenylate cyclase-stimulating G alpha protein / ...Adenylate cyclase-inhibiting G alpha protein / Adenylate cyclase-stimulating G alpha protein / Guanine nucleotide-binding protein alpha-q


Mass: 41664.285 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: the aa 1-19 and 61-180 are chimera of Guanine nucleotide-binding protein G(i) subunit alpha-1; the aa 20-60 and 181-346 are chimera of Guanine nucleotide-binding protein G(s) subunit alpha; ...Details: the aa 1-19 and 61-180 are chimera of Guanine nucleotide-binding protein G(i) subunit alpha-1; the aa 20-60 and 181-346 are chimera of Guanine nucleotide-binding protein G(s) subunit alpha; the aa 347-361 are the C terminal (345-359) of Guanine nucleotide-binding protein G(q) subunit alpha
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1, GNAS, GNAS1, GSP, GNAQ, GAQ / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P63096, UniProt: P63092, UniProt: P50148, Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement

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Protein , 1 types, 1 molecules R

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


Mass: 52648.945 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

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Non-polymers , 3 types, 15 molecules

#5: Chemical ChemComp-A1EK5 / (2~{R})-1-(4-iodanyl-2,5-dimethoxy-phenyl)propan-2-amine


Mass: 321.155 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H16INO2 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H46O
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 13 / Source method: isolated from a natural source / Formula: H2O

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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-HT2AR-bound DOI in complex with Gi heterotrimer / Type: COMPLEX / Entity ID: #1-#4 / 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: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1200 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.19.2_4158model refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.76 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 238373 / Symmetry type: POINT
RefinementHighest resolution: 2.76 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0037057
ELECTRON MICROSCOPYf_angle_d0.5799581
ELECTRON MICROSCOPYf_dihedral_angle_d4.944985
ELECTRON MICROSCOPYf_chiral_restr0.0421116
ELECTRON MICROSCOPYf_plane_restr0.0041203

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