8z7y
From Proteopedia
SLC19A3-Fedratinib inward structure
Structural highlights
DiseaseS19A3_HUMAN Thiamine-responsive encephalopathy;Biotin-thiamine-responsive basal ganglia disease;Infantile spasms-psychomotor retardation-progressive brain atrophy-basal ganglia disease syndrome. The disease is caused by variants affecting the gene represented in this entry. FunctionS19A3_HUMAN Mediates high affinity thiamine uptake, probably via a proton anti-port mechanism (PubMed:11731220, PubMed:33008889, PubMed:35512554, PubMed:35724964). Has no folate transport activity (PubMed:11731220). Mediates H(+)-dependent pyridoxine transport (PubMed:33008889, PubMed:35512554, PubMed:35724964, PubMed:36456177).[1] [2] [3] [4] [5] Publication Abstract from PubMedThiamine 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. Substrate transport and drug interaction of human thiamine transporters SLC19A2/A3.,Li P, Zhu Z, Wang Y, Zhang X, Yang C, Zhu Y, Zhou Z, Chao Y, Long Y, Gao Y, Liu S, Zhang L, Gao P, Qu Q Nat Commun. 2024 Dec 30;15(1):10924. doi: 10.1038/s41467-024-55359-8. PMID:39738067[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Homo sapiens | Large Structures | Gao P | Li PP | Qu QH | Wang Y | Zhu ZN
