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- EMDB-52213: Cryo-EM structure of domperidone-bound human SLC19A3 in inward-op... -

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Basic information

Entry
Database: EMDB / ID: EMD-52213
TitleCryo-EM structure of domperidone-bound human SLC19A3 in inward-open state
Map data
Sample
  • Complex: hSLC19A3:Nb3.3:domperidone
    • Protein or peptide: Nb3.3
    • Protein or peptide: Thiamine transporter 2
  • Ligand: 6-chloranyl-3-[1-[3-(2-oxidanylidene-3~{H}-benzimidazol-1-yl)propyl]piperidin-4-yl]-1~{H}-benzimidazol-2-one
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsThiamine transporter / drug interaction / thiamine deficiency / MEMBRANE PROTEIN
Function / homology
Function and homology information


pyridoxine transport / thiamine-containing compound metabolic process / Vitamin B1 (thiamin) metabolism / thiamine transmembrane transport / thiamine transmembrane transporter activity / thiamine transport / thiamine diphosphate biosynthetic process / transmembrane transport / membrane / plasma membrane
Similarity search - Function
Thiamine transporter 2 / Reduced folate carrier / Reduced folate carrier / MFS transporter superfamily
Similarity search - Domain/homology
Thiamine transporter 2
Similarity search - Component
Biological speciesHomo sapiens (human) / Lama glama (llama)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.35 Å
AuthorsGabriel F / Loew C
Funding support1 items
OrganizationGrant numberCountry
Other government
CitationJournal: Br J Pharmacol / Year: 2025
Title: Structure-based discovery of thiamine uptake inhibitors.
Authors: Florian Gabriel / Björn Windshügel / Christian Löw /
Abstract: BACKGROUND AND PURPOSE: Thiamine (vitamin B) is an essential coenzyme and catalyses various reactions in central metabolic pathways. Since mammals have lost the ability to synthesise thiamine de ...BACKGROUND AND PURPOSE: Thiamine (vitamin B) is an essential coenzyme and catalyses various reactions in central metabolic pathways. Since mammals have lost the ability to synthesise thiamine de novo, this micronutrient has to be imported via the high affinity solute carriers SLC19A2 and A3 across the plasma membrane. Perturbations of these transport systems have severe effects on human health. Recent structural work on SLC19A2 and A3 have provided molecular insights into substrate and drug recognition and conformational changes during transport. Based on the analysis of the available SLC19A3 structures, we hypothesise that the binding site is rather promiscuous, allowing different small molecules to interact and potentially inhibit this transporter.
EXPERIMENTAL APPROACH: We employed a computational approach, by which 538 approved and investigational drugs were docked into an ensemble of SLC19A3 cryo-EM structures, followed by experimental ...EXPERIMENTAL APPROACH: We employed a computational approach, by which 538 approved and investigational drugs were docked into an ensemble of SLC19A3 cryo-EM structures, followed by experimental binding studies, transport inhibition assays, and structural validation.
KEY RESULTS: Eight novel compounds were identified that bind and inhibit SLC19A3. To visualise such a new drug interaction, we determined the cryo-EM structure of SLC19A3 bound to domperidone, a ...KEY RESULTS: Eight novel compounds were identified that bind and inhibit SLC19A3. To visualise such a new drug interaction, we determined the cryo-EM structure of SLC19A3 bound to domperidone, a dopamine D receptor antagonist used for the treatment of nausea and gastrointestinal disorders. Our computational work together with biochemical and cellular transport assays expands the understanding of SLC19A3-drug interactions, highlights the power of virtual screening approaches using structural ensembles, and provides a three-dimensional pharmacophore model for SLC19A3 inhibitors.
CONCLUSION AND IMPLICATIONS: These findings offer a basis for addressing drug-induced thiamine deficiencies and pre approach can be used to optimise pharmacological strategies involving SLC19A3- ...CONCLUSION AND IMPLICATIONS: These findings offer a basis for addressing drug-induced thiamine deficiencies and pre approach can be used to optimise pharmacological strategies involving SLC19A3-interacting compounds in the future.
History
DepositionNov 28, 2024-
Header (metadata) releaseJul 30, 2025-
Map releaseJul 30, 2025-
UpdateOct 22, 2025-
Current statusOct 22, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_52213.png

Downloads & links

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Map

FileDownload / File: emd_52213.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 384 pix.
= 318.72 Å		0.83 Å/pix.
x 384 pix.
= 318.72 Å		0.83 Å/pix.
x 384 pix.
= 318.72 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.5
Minimum - Maximum-6.531221 - 7.6340175
Average (Standard dev.)-0.0011267402 (±0.06283112)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 318.72 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_52213_msk_1.map
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Half map: #2

Fileemd_52213_half_map_1.map
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Half map: #1

Fileemd_52213_half_map_2.map
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Sample components

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Entire : hSLC19A3:Nb3.3:domperidone

EntireName: hSLC19A3:Nb3.3:domperidone
Components
  • Complex: hSLC19A3:Nb3.3:domperidone
    • Protein or peptide: Nb3.3
    • Protein or peptide: Thiamine transporter 2
  • Ligand: 6-chloranyl-3-[1-[3-(2-oxidanylidene-3~{H}-benzimidazol-1-yl)propyl]piperidin-4-yl]-1~{H}-benzimidazol-2-one
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: hSLC19A3:Nb3.3:domperidone

SupramoleculeName: hSLC19A3:Nb3.3:domperidone / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Nb3.3

MacromoleculeName: Nb3.3 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Lama glama (llama)
Molecular weightTheoretical: 15.205778 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
QVQLVESGGG LVQAGDSLRL SCAASGRTFS NYYMAWFRQA PGKEREFVAA IRLSYGSTYY ADSVRGRFTI SKDNAKNTVN LRMNSLKSE DTAIYYCAAA EDRWALAVRT ATTYNYWGQG TQVTVSSHHH HHHEPEA

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Macromolecule #2: Thiamine transporter 2

MacromoleculeName: Thiamine transporter 2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 59.687609 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MDCYRTSLSS SWIYPTVILC LFGFFSMMRP SEPFLIPYLS GPDKNLTSAE ITNEIFPVWT YSYLVLLLPV FVLTDYVRYK PVIILQGIS FIITWLLLLF GQGVKTMQVV EFFYGMVTAA EVAYYAYIYS VVSPEHYQRV SGYCRSVTLA AYTAGSVLAQ L LVSLANMS ...String:
MDCYRTSLSS SWIYPTVILC LFGFFSMMRP SEPFLIPYLS GPDKNLTSAE ITNEIFPVWT YSYLVLLLPV FVLTDYVRYK PVIILQGIS FIITWLLLLF GQGVKTMQVV EFFYGMVTAA EVAYYAYIYS VVSPEHYQRV SGYCRSVTLA AYTAGSVLAQ L LVSLANMS YFYLNVISLA SVSVAFLFSL FLPMPKKSMF FHAKPSREIK KSSSVNPVLE ETHEGEAPGC EEQKPTSEIL ST SGKLNKG QLNSLKPSNV TVDVFVQWFQ DLKECYSSKR LFYWSLWWAF ATAGFNQVLN YVQILWDYKA PSQDSSIYNG AVE AIATFG GAVAAFAVGY VKVNWDLLGE LALVVFSVVN AGSLFLMHYT ANIWACYAGY LIFKSSYMLL ITIAVFQIAV NLNV ERYAL VFGINTFIAL VIQTIMTVIV VDQRGLNLPV SIQFLVYGSY FAVIAGIFLM RSMYITYSTK SQKDVQSPAP SENPD VSHP EEESNIIMST KLLEVLFQGP SSGWSHPQFE KGGGSGGGSG GSAWSHPQFE K

UniProtKB: Thiamine transporter 2

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Macromolecule #3: 6-chloranyl-3-[1-[3-(2-oxidanylidene-3~{H}-benzimidazol-1-yl)prop...

MacromoleculeName: 6-chloranyl-3-[1-[3-(2-oxidanylidene-3~{H}-benzimidazol-1-yl)propyl]piperidin-4-yl]-1~{H}-benzimidazol-2-one
type: ligand / ID: 3 / Number of copies: 1 / Formula: A1IVJ
Molecular weightTheoretical: 425.911 Da

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Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 1 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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: 7.4
Details: 20 mM Tris-HCl, 150 mM NaCl, 0.002% LMNG, 0.0002% CHS, 0.25 mM domperidone
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k 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: 1.7 µm / Nominal defocus min: 0.5 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: 3.35 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 427625
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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