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- PDB-9hjd: Cryo-EM structure of domperidone-bound human SLC19A3 in inward-op... -

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Basic information

Entry
Database: PDB / ID: 9hjd
TitleCryo-EM structure of domperidone-bound human SLC19A3 in inward-open state
Components
  • Nb3.3
  • Thiamine transporter 2
KeywordsMEMBRANE PROTEIN / Thiamine transporter / drug interaction / thiamine deficiency
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 speciesLama glama (llama)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.35 Å
AuthorsGabriel, F. / Loew, C.
Funding support1items
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, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 30, 2025Provider: repository / Type: Initial release
Revision 1.0Jul 30, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jul 30, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jul 30, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 30, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 30, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jul 30, 2025Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Jul 30, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Oct 22, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Nb3.3
A: Thiamine transporter 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,5414
Polymers74,8932
Non-polymers6472
Water00
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 Nb3.3


Mass: 15205.778 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)
#2: Protein Thiamine transporter 2 / ThTr-2 / ThTr2 / Solute carrier family 19 member 3


Mass: 59687.609 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC19A3 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9BZV2
#3: Chemical ChemComp-A1IVJ / 6-chloranyl-3-[1-[3-(2-oxidanylidene-3~{H}-benzimidazol-1-yl)propyl]piperidin-4-yl]-1~{H}-benzimidazol-2-one


Mass: 425.911 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H24ClN5O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
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: hSLC19A3:Nb3.3:domperidone / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.4
Details: 20 mM Tris-HCl, 150 mM NaCl, 0.002% LMNG, 0.0002% CHS, 0.25 mM domperidone
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE-PROPANE

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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: 1700 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 3.35 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 427625 / Symmetry type: POINT
RefinementResolution: 3.35→3.35 Å / Cor.coef. Fo:Fc: 0.473 / WRfactor Rwork: 0.521 / Average fsc free: 0 / Average fsc overall: 0.5236 / Average fsc work: 0.5236 / ESU R: 0.086
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rwork0.5212 1725401 -
all0.521 --
Rfree--0 %
obs--100 %
Solvent computationSolvent model: NONE
Displacement parametersBiso mean: 39.364 Å2
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0090.0124190
ELECTRON MICROSCOPYr_bond_other_d0.0020.0163931
ELECTRON MICROSCOPYr_angle_refined_deg1.4221.7935719
ELECTRON MICROSCOPYr_angle_other_deg0.7711.7018969
ELECTRON MICROSCOPYr_dihedral_angle_1_deg4.8555504
ELECTRON MICROSCOPYr_dihedral_angle_2_deg0.925518
ELECTRON MICROSCOPYr_dihedral_angle_3_deg15.29410632
ELECTRON MICROSCOPYr_dihedral_angle_6_deg17.34810171
ELECTRON MICROSCOPYr_chiral_restr0.0540.2646
ELECTRON MICROSCOPYr_gen_planes_refined0.0070.024881
ELECTRON MICROSCOPYr_gen_planes_other0.0110.021073
ELECTRON MICROSCOPYr_nbd_refined0.2340.21161
ELECTRON MICROSCOPYr_symmetry_nbd_other0.2220.23877
ELECTRON MICROSCOPYr_nbtor_refined0.2130.22222
ELECTRON MICROSCOPYr_symmetry_nbtor_other0.0860.22248
ELECTRON MICROSCOPYr_xyhbond_nbd_refined0.1690.265
ELECTRON MICROSCOPYr_mcbond_it042025
ELECTRON MICROSCOPYr_mcbond_other042025
ELECTRON MICROSCOPYr_mcangle_it07.1732526
ELECTRON MICROSCOPYr_mcangle_other07.1732527
ELECTRON MICROSCOPYr_scbond_it042165
ELECTRON MICROSCOPYr_scbond_other042166
ELECTRON MICROSCOPYr_scangle_it07.3653193
ELECTRON MICROSCOPYr_scangle_other07.3653194
ELECTRON MICROSCOPYr_lrange_it047.59217131
ELECTRON MICROSCOPYr_lrange_other047.59117132
LS refinement shell

Refine-ID: ELECTRON MICROSCOPY / Num. reflection Rfree: _ / Total num. of bins used: 20 / % reflection obs: 100 %

Resolution (Å)Rfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc workWRfactor Rwork
3.4-3.4880.7031279960.7031279960.180.703
3.488-3.5840.6351245250.6351245250.2510.635
3.584-3.6880.5831202720.5831202720.3290.583
3.688-3.8010.5351178290.5351178290.3980.535
3.801-3.9260.4981139660.4981139660.4740.498
3.926-4.0640.4841102450.4841102450.5550.484
4.064-4.2170.4871067090.4871067090.630.487
4.217-4.3890.4911020530.4911020530.6810.491
4.389-4.5840.49978490.49978490.7020.49
4.584-4.8080.492942230.492942230.7070.492
4.808-5.0680.486892760.486892760.6870.486
5.068-5.3760.475840230.475840230.6390.475
5.376-5.7470.474794840.474794840.5550.474
5.747-6.2070.49737820.49737820.4920.49
6.207-6.7990.509677570.509677570.5010.509
6.799-7.6010.507612990.507612990.5860.507
7.601-8.7760.513541750.513541750.6830.513
8.776-10.7460.533457350.533457350.7630.533
10.746-15.1890.687352430.687352430.7890.687
15.189-318.720.837193200.837193200.5590.837

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