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- PDB-8z80: SLC19A2-Pyridoxine inward structure -

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Basic information

Entry
Database: PDB / ID: 8z80
TitleSLC19A2-Pyridoxine inward structure
ComponentsThiamine transporter 1
KeywordsMEMBRANE PROTEIN / Thiamine transporter / MFS
Function / homology
Function and homology information


folic acid transmembrane transporter activity / 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 / spermatogenesis ...folic acid transmembrane transporter activity / 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 / spermatogenesis / membrane / plasma membrane
Similarity search - Function
Thiamine transporter 1 / Reduced folate carrier / Reduced folate carrier / MFS transporter superfamily
Similarity search - Domain/homology
4,5-bis(hydroxymethyl)-2-methyl-pyridin-3-ol / Thiamine transporter 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsLi, P.P. / Zhu, Z.N. / Wang, Y. / Gao, P. / Qu, Q.H.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Commun / Year: 2024
Title: Substrate transport and drug interaction of human thiamine transporters SLC19A2/A3.
Authors: Peipei Li / Zhini Zhu / Yong Wang / Xuyuan Zhang / Chuanhui Yang / Yalan Zhu / Zixuan Zhou / Yulin Chao / Yonghui Long / Yina Gao / Songqing Liu / Liguo Zhang / Pu Gao / Qianhui Qu /
Abstract: Thiamine and pyridoxine are essential B vitamins that serve as enzymatic cofactors in energy metabolism, protein and nucleic acid biosynthesis, and neurotransmitter production. In humans, thiamine ...Thiamine and pyridoxine are essential B vitamins that serve as enzymatic cofactors in energy metabolism, protein and nucleic acid biosynthesis, and neurotransmitter production. In humans, thiamine transporters SLC19A2 and SLC19A3 primarily regulate cellular uptake of both vitamins. Genetic mutations in these transporters, which cause thiamine and pyridoxine deficiency, have been implicated in severe neurometabolic diseases. Additionally, various prescribed medicines, including metformin and fedratinib, manipulate thiamine transporters, complicating the therapeutic effect. Despite their physiological and pharmacological significance, the molecular underpinnings of substrate and drug recognition remain unknown. Here we present ten cryo-EM structures of human thiamine transporters SLC19A3 and SLC19A2 in outward- and inward-facing conformations, complexed with thiamine, pyridoxine, metformin, fedratinib, and amprolium. These structural insights, combined with functional characterizations, illuminate the translocation mechanism of diverse chemical entities, and enhance our understanding of drug-nutrient interactions mediated by thiamine transporters.
History
DepositionApr 21, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jan 8, 2025Provider: repository / Type: Initial release
Revision 1.0Jan 8, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jan 8, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 8, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 8, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jan 8, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Jul 16, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1Jul 16, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Thiamine transporter 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,6022
Polymers55,4331
Non-polymers1691
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: Protein Thiamine transporter 1 / ThTr-1 / ThTr1 / Solute carrier family 19 member 2 / Thiamine carrier 1 / TC1


Mass: 55432.605 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC19A2, THT1, TRMA / Production host: Homo sapiens (human) / References: UniProt: O60779
#2: Chemical ChemComp-UEG / 4,5-bis(hydroxymethyl)-2-methyl-pyridin-3-ol


Mass: 169.178 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H11NO3 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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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: SLC19A3-Thiamine complex / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 6
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: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 157332 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0032895
ELECTRON MICROSCOPYf_angle_d0.7093983
ELECTRON MICROSCOPYf_dihedral_angle_d5.082416
ELECTRON MICROSCOPYf_chiral_restr0.044497
ELECTRON MICROSCOPYf_plane_restr0.006483

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