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Structure paper

TitleSubstrate transport and drug interaction of human thiamine transporters SLC19A2/A3.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 10924, Year 2024
Publish dateDec 30, 2024
AuthorsPeipei 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 /
PubMed AbstractThiamine 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.
External linksNat Commun / PubMed:39738067 / PubMed Central
MethodsEM (single particle)
Resolution3.02 - 3.7 Å
Structure data

39825

8z7r

EMDB-39825, PDB-8z7r:
SLC19A3 apo structure
Method: EM (single particle) / Resolution: 3.15 Å

39826

8z7s

EMDB-39826, PDB-8z7s:
SLC19A3-thiamine outward structure
Method: EM (single particle) / Resolution: 3.05 Å

39827

8z7t

EMDB-39827, PDB-8z7t:
SLC19A3-Pyridoxine outward structure
Method: EM (single particle) / Resolution: 3.39 Å

39828

8z7u

EMDB-39828, PDB-8z7u:
SLC19A3-Fedratinib outward structure
Method: EM (single particle) / Resolution: 3.1 Å

39829

8z7v

EMDB-39829, PDB-8z7v:
Slc19A3-Amprolium outward structure
Method: EM (single particle) / Resolution: 3.1 Å

39830

8z7w

EMDB-39830, PDB-8z7w:
SLC19A3-Metformin outward structure
Method: EM (single particle) / Resolution: 3.09 Å

39831

8z7x

EMDB-39831, PDB-8z7x:
SLC19A3-Thiamine inward structure
Method: EM (single particle) / Resolution: 3.36 Å

39832

8z7y

EMDB-39832, PDB-8z7y:
SLC19A3-Fedratinib inward structure
Method: EM (single particle) / Resolution: 3.02 Å

39833

8z7z

EMDB-39833, PDB-8z7z:
SLC19A2-Thiamine inward structure
Method: EM (single particle) / Resolution: 3.23 Å

39834

8z80

EMDB-39834, PDB-8z80:
SLC19A2-Pyridoxine inward structure
Method: EM (single particle) / Resolution: 3.7 Å

Chemicals

ChemComp-VIB:
3-(4-AMINO-2-METHYL-PYRIMIDIN-5-YLMETHYL)-5-(2-HYDROXY-ETHYL)-4-METHYL-THIAZOL-3-IUM / medication*YM

ChemComp-UEG:
4,5-bis(hydroxymethyl)-2-methyl-pyridin-3-ol

ChemComp-2TA:
N-tert-butyl-3-{[5-methyl-2-({4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}amino)pyrimidin-4-yl]amino}benzenesulfonamide / medication, anticancer*YM

PDB-1h5c:
X-ray induced reduction of horseradish peroxidase C1A Compound III (100-200% dose)

ChemComp-MF8:
Metformin / medication, antipsychotic*YM

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Thiamine transporter / MFS

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