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- PDB-8z7w: SLC19A3-Metformin outward structure -

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Basic information

Entry
Database: PDB / ID: 8z7w
TitleSLC19A3-Metformin outward structure
ComponentsThiamine transporter 2
KeywordsMEMBRANE PROTEIN / Thiamine transporter / MFS
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
Metformin / Thiamine transporter 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.09 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Thiamine transporter 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,8282
Polymers55,6991
Non-polymers1291
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 2 / ThTr-2 / ThTr2 / Solute carrier family 19 member 3


Mass: 55699.316 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC19A3 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9BZV2
#2: Chemical ChemComp-MF8 / Metformin / N,N-Dimethylimidodicarbonimidic diamide


Mass: 129.164 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H11N5 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, antipsychotic*YM
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 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
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: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1500 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.09 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 252244 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0043199
ELECTRON MICROSCOPYf_angle_d0.6384372
ELECTRON MICROSCOPYf_dihedral_angle_d4.696423
ELECTRON MICROSCOPYf_chiral_restr0.042505
ELECTRON MICROSCOPYf_plane_restr0.008524

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