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- PDB-9kvh: A Cryo_EM structure of 5_HT1A complex with TMT -

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Basic information

Entry
Database: PDB / ID: 9kvh
TitleA Cryo_EM structure of 5_HT1A complex with TMT
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • 5-hydroxytryptamine receptor 1A
  • SCFV16
KeywordsMEMBRANE PROTEIN / GPCR / 5_HT1A
Function / homology
Function and homology information


regulation of serotonin secretion / Gi/o-coupled serotonin receptor activity / regulation of hormone secretion / regulation of behavior / receptor-receptor interaction / regulation of dopamine metabolic process / serotonin receptor activity / Serotonin receptors / G protein-coupled serotonin receptor activity / serotonin receptor signaling pathway ...regulation of serotonin secretion / Gi/o-coupled serotonin receptor activity / regulation of hormone secretion / regulation of behavior / receptor-receptor interaction / regulation of dopamine metabolic process / serotonin receptor activity / Serotonin receptors / G protein-coupled serotonin receptor activity / serotonin receptor signaling pathway / neurotransmitter receptor activity / serotonin binding / serotonin metabolic process / exploration behavior / behavioral fear response / regulation of vasoconstriction / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / regulation of eating behavior / adenylate cyclase inhibitor activity / T cell migration / positive regulation of protein localization to cell cortex / positive regulation of relaxation of smooth muscle / Adenylate cyclase inhibitory pathway / D2 dopamine receptor binding / adenylate cyclase-inhibiting serotonin receptor signaling pathway / G protein-coupled serotonin receptor binding / cellular response to forskolin / regulation of mitotic spindle organization / mast cell degranulation / chemokine-mediated signaling pathway / neuropeptide signaling pathway / Regulation of insulin secretion / response to prostaglandin E / positive regulation of cholesterol biosynthetic process / G protein-coupled receptor binding / response to peptide hormone / G-protein beta/gamma-subunit complex binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G protein-coupled acetylcholine receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / GDP binding / G beta:gamma signalling through BTK / photoreceptor disc membrane / ADP signalling through P2Y purinoceptor 12 / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / G alpha (12/13) signalling events / G-protein beta-subunit binding / extracellular vesicle / Thrombin signalling through proteinase activated receptors (PARs) / signaling receptor complex adaptor activity / adenylate cyclase-activating G protein-coupled receptor signaling pathway / GTPase binding / G protein activity / midbody / chemical synaptic transmission / Ca2+ pathway / cell cortex / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / ciliary basal body / G alpha (s) signalling events / G alpha (q) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / Ras protein signal transduction / Extra-nuclear estrogen signaling / G protein-coupled receptor signaling pathway / cell division / lysosomal membrane / GTPase activity / centrosome / positive regulation of cell population proliferation / synapse / dendrite
Similarity search - Function
5-Hydroxytryptamine 1A receptor / 5-hydroxytryptamine receptor family / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / G-protein, gamma subunit ...5-Hydroxytryptamine 1A receptor / 5-hydroxytryptamine receptor family / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / 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 / Chem-J40 / 5-hydroxytryptamine receptor 1A / 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(i) subunit alpha-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.59 Å
AuthorsYuan, Q. / Li, S.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Research (Wash D C) / Year: 2025
Title: Structural Pharmacology of Bufotenine Derivatives in Activating the 5-HT Receptor for Therapeutic Potential in Depression and Anxiety.
Authors: Shu-Jie Li / Qing-Ning Yuan / Wen-Yuan Wu / Zhi-Han Chen / Duo Chen / Hong Shan / Qin-Yu Chu / Wen Hu / Kai Wu / Tao Liu / Yu-Yu Zhu / Li Hou / Jing Zhou / Jia Duan / Jin-Ao Duan / H Eric Xu / Hong-Yue Ma /
Abstract: The 5-HT receptor is a critical target in the treatment of depression and anxiety. Bufotenine derivatives, such as 5-methoxy-,-dimethyltryptamine (5-MeO-DMT), 5-hydroxy-,-dimethyltryptamine (5-OH-DMT) ...The 5-HT receptor is a critical target in the treatment of depression and anxiety. Bufotenine derivatives, such as 5-methoxy-,-dimethyltryptamine (5-MeO-DMT), 5-hydroxy-,-dimethyltryptamine (5-OH-DMT), and 5-hydroxy-,,-dimethyltryptamine-derived from traditional Chinese medicine-have shown antidepressant potential. However, the structural basis of their interaction with 5-HT and their pharmacological profiles remain incompletely understood. This study investigated bufotenine derivatives acting on multiple serotonin receptors, highlighting 5-HT as a key mediator of antidepressant effects while recognizing 5-HT as primarily responsible for hallucinogenic outcomes, to identify candidates with therapeutic efficacy but reduced hallucinogenic liability. We determined the cryo-electron microscopy structures of 5-HT bound to selected bufotenine derivatives. Functional assays in mice, including behavioral tests and receptor activation studies, were used to evaluate the antidepressant of each compound. Structural analysis revealed that all bufotenine derivatives engage conserved motifs within the 5-HT binding pocket, with 5-OH-DMT displaying a distinct interaction pattern. Behavioral assays showed that 5-OH-DMT and 5-MeO-DMT retained strong antidepressant and anxiolytic effects. These pharmacological differences correlate with their unique receptor binding conformation. This study delineated the structural pharmacology of bufotenine derivatives at the 5-HT receptor, identifying 5-OH-DMT and 5-MeO-DMT as promising antidepressant and anxiolytic candidates. The findings establish a molecular framework for the development of next-generation nonhallucinogenic therapeutics aimed at 5-HT.
History
DepositionDec 5, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Dec 3, 2025Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(i) subunit alpha-1
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
E: SCFV16
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
R: 5-hydroxytryptamine receptor 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)158,0499
Polymers156,1385
Non-polymers1,9104
Water1448
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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

#1: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40356.016 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P63096, Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37784.301 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
#4: 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

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Antibody / Protein , 2 types, 2 molecules ER

#3: Antibody SCFV16


Mass: 26277.299 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)
#5: Protein 5-hydroxytryptamine receptor 1A / 5-HT-1A / 5-HT1A / G-21 / Serotonin receptor 1A


Mass: 43859.285 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HTR1A, ADRB2RL1, ADRBRL1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P08908

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Non-polymers , 5 types, 12 molecules

#6: Chemical ChemComp-A1EG9 / Cinobufotenine / N,N,N-Trimethylserotonin


Mass: 219.303 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H19N2O / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical ChemComp-J40 / [(2R)-1-[oxidanyl-[(2R,3R,5S,6R)-2,3,5,6-tetrakis(oxidanyl)-4-phosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-3-tetradecanoyloxy-propan-2-yl] (5E,8E)-hexadeca-5,8,11,14-tetraenoate


Mass: 854.895 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C39H68O16P2 / Feature type: SUBJECT OF INVESTIGATION
#8: Chemical ChemComp-CHO / GLYCOCHENODEOXYCHOLIC ACID


Mass: 449.623 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H43NO5 / Feature type: SUBJECT OF INVESTIGATION / Comment: detergent*YM
#9: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H46O / Feature type: SUBJECT OF INVESTIGATION
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 8 / 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: A cryo_EM structure 5-HT1A complex with TMT / Type: COMPLEX / Entity ID: #1-#5 / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.04
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: 18000 nm / Nominal defocus min: 8000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON III (4k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487 / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.59 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 139905 / Symmetry type: POINT
RefinementHighest resolution: 2.59 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0018975
ELECTRON MICROSCOPYf_angle_d0.37512154
ELECTRON MICROSCOPYf_dihedral_angle_d9.3473230
ELECTRON MICROSCOPYf_chiral_restr0.0391382
ELECTRON MICROSCOPYf_plane_restr0.0031536

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