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- EMDB-46618: The TBZ-bound structure -

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Basic information

Entry
Database: EMDB / ID: EMD-46618
TitleThe TBZ-bound structure
Map dataTBZ-bound structure
Sample
  • Organelle or cellular component: fusion protein
    • Protein or peptide: Green fluorescence protein,MFS-type transporter SLC18B1,membrane protein with TBZ
  • Ligand: tetrabenazine
  • Ligand: water
Keywordsmembrane protein
Function / homology
Function and homology information


polyamine:proton antiporter activity / spermidine transport / spermine transport / monoamine:proton antiporter activity / serotonin uptake / transmembrane transporter activity / bioluminescence / secretory granule membrane / generation of precursor metabolites and energy / synaptic vesicle 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 fluorescence protein / MFS-type transporter SLC18B1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsLu M / Liu B
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM145642 United States
CitationJournal: Nat Commun / Year: 2025
Title: Structure and mechanism of human vesicular polyamine transporter.
Authors: Yi Guo / Ge Yang / Haijiao Liu / Jin Chai / Jie Chen / John Shanklin / Qun Liu / Bin Liu / Min Lu /
Abstract: Polyamines play essential roles in gene expression and modulate neuronal transmission in mammals. Vesicular polyamine transporters (VPAT) from the SLC18 family exploit the transmembrane H gradient to ...Polyamines play essential roles in gene expression and modulate neuronal transmission in mammals. Vesicular polyamine transporters (VPAT) from the SLC18 family exploit the transmembrane H gradient to translocate polyamines into secretory vesicles, enabling the quantal release of polyamine neuromodulators and underpinning learning and memory formation. Here, we report the cryo-electron microscopy structures of human VPAT in complex with spermine, spermidine, H, or tetrabenazine, elucidating discrete lumen-facing states of the antiporter and pivotal interactions between VPAT and its substrate or inhibitor. Leveraging structure-inspired mutagenesis studies and protein structure prediction, we deduce an unforeseen mechanism whereby the polyamine and H compete for multiple acidic protein residues both directly and indirectly, and rationalize how the antidopaminergic therapeutic tetrabenazine impedes vesicular transport of polyamines. This study unravels the mechanism of an H-coupled polyamine antiporter, reveals mechanistic diversity between VPAT and other SLC18 antiporters, and raises new prospects for combating human disorders of polyamine homeostasis.
History
DepositionAug 17, 2024-
Header (metadata) releaseJun 25, 2025-
Map releaseJun 25, 2025-
UpdateJun 25, 2025-
Current statusJun 25, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_46618.png

Downloads & links

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Map

FileDownload / File: emd_46618.map.gz / Format: CCP4 / Size: 86.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationTBZ-bound structure
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1 Å/pix.
x 283 pix.
= 283.307 Å		1 Å/pix.
x 283 pix.
= 283.307 Å		1 Å/pix.
x 283 pix.
= 283.307 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.00108 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 6.0
Minimum - Maximum-0.5503304 - 27.387329999999999
Average (Standard dev.)0.029779887 (±0.4875523)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions283283283
Spacing283283283
CellA=B=C: 283.30664 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map A

Fileemd_46618_half_map_1.map
AnnotationHalf Map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map B

Fileemd_46618_half_map_2.map
AnnotationHalf Map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : fusion protein

EntireName: fusion protein
Components
  • Organelle or cellular component: fusion protein
    • Protein or peptide: Green fluorescence protein,MFS-type transporter SLC18B1,membrane protein with TBZ
  • Ligand: tetrabenazine
  • Ligand: water

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Supramolecule #1: fusion protein

SupramoleculeName: fusion protein / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 90 kDa/nm

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Macromolecule #1: Green fluorescence protein,MFS-type transporter SLC18B1,membrane ...

MacromoleculeName: Green fluorescence protein,MFS-type transporter SLC18B1,membrane protein with TBZ
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 82.119766 KDa
Recombinant expressionOrganism: Insect cell expression vector pTIE1 (others)
SequenceString: VSKGEELFTG VVPILVELDG DVNGHKFSVS GEGEGDATYG KLTLKLICTT GKLPVPWPTL VTTLGYGLQC FARYPDHMKQ HDFFKSAMP EGYVQERTIF FKDDGNYKTR AEVKFEGDTL VNRIELKGID FKEDGNILGH KLEYNYNSHN VYITADKQKN G IKANFKIR ...String:
VSKGEELFTG VVPILVELDG DVNGHKFSVS GEGEGDATYG KLTLKLICTT GKLPVPWPTL VTTLGYGLQC FARYPDHMKQ HDFFKSAMP EGYVQERTIF FKDDGNYKTR AEVKFEGDTL VNRIELKGID FKEDGNILGH KLEYNYNSHN VYITADKQKN G IKANFKIR HNIEDGGVQL ADHYQQNTPI GDGPVLLPDN HYLSYQSKLS KDPNEKRDHM VLLEFVTAAG ITTPGWLSRE QV FVLISAA SVNLGSMMCY SILGPFFPKE AEKKGASNTI IGMIFGCFAL FELLASLVFG NYLVHIGAKF MFVAGMFVSG GVT ILFGVL DRVPDGPVFI AMCFLVRVMD AVSFAAAMTA SSSILAKAFP NNVATVLGSL ETFSGLGLIL GPPVGGFLYQ SFGY EVPFI VLGCVVLLMV PLNMYILPNY ESDPGEHSFW KLIALPKVGL IAFVINSLSS CFGFLDPTLS LFVLEKFNLP AGYVG LVFL GMALSYAISS PLFGLLSDKR PPLRKWLLVF GNLITAGCYM LLGPVPILHI KSQLWLLVLI LVVSGLSAGM SIIPTF PEI LSCAHENGFE EGLSTLGLVS GLFSAMWSIG AFMGPTLGGF LYEKIGFEWA AAIQGLWALI SGLAMGLFYL LEYSQVQ LV ESGGALVQPG GSLRLSCAAS GFPVNRYSMR WYRQAPGKER EWVAGMSSAG DRSSYEDSVK GRFTISRDDA RNTVYLQM N SLKPEDTAVY YCNVNVGFEY WGQGTQVTVS

UniProtKB: Green fluorescence protein, MFS-type transporter SLC18B1

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Macromolecule #2: tetrabenazine

MacromoleculeName: tetrabenazine / type: ligand / ID: 2 / Number of copies: 1 / Formula: YHL
Molecular weightTheoretical: 317.423 Da
Chemical component information

ChemComp-YHL:
tetrabenazine

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Macromolecule #3: water

MacromoleculeName: water / type: ligand / ID: 3 / Number of copies: 4 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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: 4.9
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 30.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / 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: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 79000
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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