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- PDB-9d7w: The TBZ-bound structure -

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Basic information

Entry
Database: PDB / ID: 9d7w
TitleThe TBZ-bound structure
ComponentsGreen fluorescence protein,MFS-type transporter SLC18B1,membrane protein with TBZ
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 / secretory granule membrane / bioluminescence / 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
tetrabenazine / Green fluorescence protein / MFS-type transporter SLC18B1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsLu, M. / Liu, B.
Funding support United States, 1items
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 25, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Green fluorescence protein,MFS-type transporter SLC18B1,membrane protein with TBZ
hetero molecules


Theoretical massNumber of molelcules
Total (without water)82,4372
Polymers82,1201
Non-polymers3171
Water724
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

#1: Antibody Green fluorescence protein,MFS-type transporter SLC18B1,membrane protein with TBZ / Solute carrier family 18 member B1 / Vesicular polyamine transporter / VPAT


Mass: 82119.766 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: APY04_3197, SLC18B1, C6orf192
Production host: Insect cell expression vector pTIE1 (others)
References: UniProt: A0A125NTU3, UniProt: Q6NT16
#2: Chemical ChemComp-YHL / tetrabenazine / (3R,5R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one


Mass: 317.423 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H27NO3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN
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: fusion protein / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 90 kDa/nm / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Insect cell expression vector pTIE1 (others)
Buffer solutionpH: 4.9
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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 30 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.21_5207: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 79000 / Symmetry type: POINT

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