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- EMDB-38651: Structure of human VAChT in complex with acetylcholine -

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Basic information

Entry
Database: EMDB / ID: EMD-38651
TitleStructure of human VAChT in complex with acetylcholine
Map data
Sample
  • Complex: transporter
    • Protein or peptide: Vesicular acetylcholine transporter,Green fluorescent protein,antibody
  • Ligand: ACETYLCHOLINE
KeywordsTransporter / Membrane protein / TRANSPORT PROTEIN
Function / homology
Function and homology information


acetylcholine:proton antiporter activity / acetylcholine uptake / clathrin-sculpted acetylcholine transport vesicle membrane / acetylcholine transmembrane transporter activity / positive regulation of neuromuscular junction development / AP-1 adaptor complex / Acetylcholine Neurotransmitter Release Cycle / monoamine:proton antiporter activity / positive regulation of acetylcholine secretion, neurotransmission / AP-2 adaptor complex ...acetylcholine:proton antiporter activity / acetylcholine uptake / clathrin-sculpted acetylcholine transport vesicle membrane / acetylcholine transmembrane transporter activity / positive regulation of neuromuscular junction development / AP-1 adaptor complex / Acetylcholine Neurotransmitter Release Cycle / monoamine:proton antiporter activity / positive regulation of acetylcholine secretion, neurotransmission / AP-2 adaptor complex / serotonin uptake / neurotransmitter transport / bioluminescence / positive regulation of long-term synaptic potentiation / generation of precursor metabolites and energy / clathrin-coated endocytic vesicle membrane / terminal bouton / Cargo recognition for clathrin-mediated endocytosis / synaptic vesicle membrane / Clathrin-mediated endocytosis / chemical synaptic transmission / plasma membrane
Similarity search - Function
: / Major facilitator superfamily / Major Facilitator Superfamily / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily / Green fluorescent protein, GFP / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein
Similarity search - Domain/homology
Green fluorescent protein / Vesicular acetylcholine transporter
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsZhao Y / Ma Q / Dong Y / Meng Y
Funding support China, 1 items
OrganizationGrant numberCountry
Chinese Academy of Sciences China
CitationJournal: Nat Struct Mol Biol / Year: 2025
Title: Binding mechanism and antagonism of the vesicular acetylcholine transporter VAChT.
Authors: Qiao Ma / Kunpeng Ma / Yanli Dong / Yufei Meng / Jun Zhao / Renjie Li / Qinru Bai / Di Wu / Daohua Jiang / Jianyuan Sun / Yan Zhao /
Abstract: The vesicular acetylcholine transporter (VAChT) has a pivotal role in packaging and transporting acetylcholine for exocytotic release, serving as a vital component of cholinergic neurotransmission. ...The vesicular acetylcholine transporter (VAChT) has a pivotal role in packaging and transporting acetylcholine for exocytotic release, serving as a vital component of cholinergic neurotransmission. Dysregulation of its function can result in neurological disorders. It also serves as a target for developing radiotracers to quantify cholinergic neuron deficits in neurodegenerative conditions. Here we unveil the cryo-electron microscopy structures of human VAChT in its apo state, the substrate acetylcholine-bound state and the inhibitor vesamicol-bound state. These structures assume a lumen-facing conformation, offering a clear depiction of architecture of VAChT. The acetylcholine-bound structure provides a detailed understanding of how VAChT recognizes its substrate, shedding light on the coupling mechanism of protonation and substrate binding. Meanwhile, the vesamicol-bound structure reveals the binding mode of vesamicol to VAChT, laying the structural foundation for the design of the next generation of radioligands targeting VAChT.
History
DepositionJan 12, 2024-
Header (metadata) releaseDec 25, 2024-
Map releaseDec 25, 2024-
UpdateJul 16, 2025-
Current statusJul 16, 2025Processing site: PDBj / Status: Released

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Structure visualization

Downloads & links

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Map

FileDownload / File: emd_38651.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.85 Å
Density
Contour LevelBy AUTHOR: 0.38
Minimum - Maximum-1.1391643 - 1.8371826
Average (Standard dev.)0.00014541238 (±0.03419315)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 255.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : transporter

EntireName: transporter
Components
  • Complex: transporter
    • Protein or peptide: Vesicular acetylcholine transporter,Green fluorescent protein,antibody
  • Ligand: ACETYLCHOLINE

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Supramolecule #1: transporter

SupramoleculeName: transporter / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Vesicular acetylcholine transporter,Green fluorescent protein,antibody

MacromoleculeName: Vesicular acetylcholine transporter,Green fluorescent protein,antibody
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 91.944422 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MESAEPAGQA RAAATKLSEA VGAALQSKGE ELFTGVVPIL VELDGDVNGH KFSVRGEGEG DATNGKLTLK FICTTGKLPV PWPTLVTTL TYGVQCFSRY PDHMKRHDFF KSAMPEGYVQ ERTISFKDDG TYKTRAEVKF EGDTLVNRIE LKGIDFKEDG N ILGHKLEY ...String:
MESAEPAGQA RAAATKLSEA VGAALQSKGE ELFTGVVPIL VELDGDVNGH KFSVRGEGEG DATNGKLTLK FICTTGKLPV PWPTLVTTL TYGVQCFSRY PDHMKRHDFF KSAMPEGYVQ ERTISFKDDG TYKTRAEVKF EGDTLVNRIE LKGIDFKEDG N ILGHKLEY NFNSHNVYIT ADKQKNGIKA NFKIRHNVED GSVQLADHYQ QNTPIGDGPV LLPDNHYLST QSVLSKDPNE KR DHMVLLE FVTAAGIEPR RQRRLVLVIV CVALLLDNML YMVIVPIVPD YIAHMRGGGE GPTRTPEVWE PTLPLPTPAN ASA YTANTS ASPTAAWPAG SALRPRYPTE SEDVKIGVLF ASKAILQLLV NPLSGPFIDR MSYDVPLLIG LGVMFASTVL FAFA EDYAT LFAARSLQGL GSAFADTSGI AMIADKYPEE PERSRALGVA LAFISFGSLV APPFGGILYE FAGKRVPFLV LAAVS LFDA LLLLAVAKPF SAAARARANL PVGTPIHRLM LDPYIAVVAG ALTTCNIPLA FLEPTIATWM KHTMAASEWE MGMAWL PAF VPHVLGVYLT VRLAARYPHL QWLYGALGLA VIGASSCIVP ACRSFAPLVV SLCGLCFGIA LVDTALLPTL AFLVDVR HV SVYGSVYAIA DISYSVAYAL GPIVAGHIVH SLGFEQLSLG MGLANLLYAP VLLLLRNVGL LTGSGQVQLV ESGGALVQ P GGSLRLSCAA SGFPVNRYSM RWYRQAPGKE REWVAGMSSA GDRSSYEDSV KGRFTISRDD ARNTVYLQMN SLKPEDTAV YYCNVNVGFE YWGQGTQVTV SMGWSHPQFE KGGGSGGGSG GSAWSHPQFE K

UniProtKB: Vesicular acetylcholine transporter, Green fluorescent protein, Vesicular acetylcholine transporter

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Macromolecule #2: ACETYLCHOLINE

MacromoleculeName: ACETYLCHOLINE / type: ligand / ID: 2 / Number of copies: 1 / Formula: ACH
Molecular weightTheoretical: 146.207 Da
Chemical component information

ChemComp-ACH:
ACETYLCHOLINE

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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

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING ONLY
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 201774
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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