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Substrate and drug recognition mechanisms of SLC19A3

Cell Research (2024)Cite this article

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A Correction to this article was published on 05 April 2024

This article has been updated

Dear Editor,

Vitamins B1 and B6 are two water-soluble vitamins. Their active forms thiamine pyrophosphate and pyridoxal 5′-phosphate serve as cofactors for numerous enzymes involved in multiple biochemical reactions that are essential to maintain the composition and energy metabolism of the human body.1 Consequently, their deficiency leads to a variety of diseases, such as neurological abnormalities and cardiovascular diseases.2 Humans cannot synthesize these vitamins de novo and must obtain them from the diet. Two specific transporters, thiamine transporter 1 (ThTr1 or SLC19A2) and thiamine transporter 2 (ThTr2 or SLC19A3), have been identified to be the major transmembrane transporters that are involved in the uptake of both vitamins thus far.3,4,5,6 Interestingly, the clinical antineoplastic drug fedratinib, a Janus kinase 2 (JAK2) inhibitor used in treating myelofibrosis, induces Wernicke’s-like encephalopathy in some myelofibrosis patients due to thiamine scarcity.7,8 This is caused by its off-target inhibitory activity against both SLC19A2 and SLC19A3.9 Here, we report the cryo-electron microscopy (cryo-EM) structures of human SLC19A3 in complex with vitamins B1, B6, or fedratinib. Remarkably, all these compounds bind to the same site on SLC19A3 via a closely related structural element. Mutagenesis studies further revealed the critical residues of SLC19A3 for substrate and drug recognition. In summary, our work provides a structural framework for understanding the substrate diversity of SLC19A3.

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Fig. 1: Molecular mechanisms of substrate recognition by SLC19A3.

Data availability

Cryo-EM density maps of thiamine-, pyridoxamine-, and fedratinib-bound SLC19A3 have been deposited in the Electron Microscopy Data Bank under the accession codes EMD-38691, EMD-38692, and EMD-38693, respectively. Their atomic coordinates have been deposited in the Protein Data Bank under accession codes 8XV2, 8XV5, and 8XV9, respectively.

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Acknowledgements

We thank the cryo-EM platform at the School of Life Sciences of Peking University for cryo-EM data collection. We thank Shitang Huang at the National Center for Protein Sciences of Peking University for assistance with radioactive experiments. We thank the High-Performance Computing Platform of Peking University for computing support. This research was funded by the National Key R&D Program of China (2021YFA1302300 to Z.Z.) and the National Natural Science Foundation of China (32171201 to Z.Z.). The study was also supported by the Center for Life Sciences, School of Life Sciences of Peking University, the State Key Laboratory of Membrane Biology of China (to Z.Z.), and ALSAC (to C.-H.L.).

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Author notes

  1. These authors contributed equally: Yu Dang, Tianyi Zhang, Shabareesh Pidathala, Guopeng Wang, Yijie Wang, Nanhao Chen.

Authors and Affiliations

  1. State Key Laboratory of Membrane Biology, Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China

    Yu Dang & Zhe Zhang

  2. School of Life Sciences, Peking University, Beijing, China

    Tianyi Zhang, Yijie Wang & Zhe Zhang

  3. Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Shabareesh Pidathala & Chia-Hsueh Lee

  4. Cryo-EM Platform, School of Life Sciences, Peking University, Beijing, China

    Guopeng Wang

  5. Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China

    Nanhao Chen & Chen Song

  6. Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China

    Chen Song & Zhe Zhang

Authors
  1. Yu Dang
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Contributions

Z.Z. conceived the research and supervised the project. Y.D., T.Z., and Y.W. performed the cloning. Y.D. and T.Z. prepared all the protein samples and collected the cryo-EM data. G.W., Y.D., and Z.Z. processed the EM data. Z.Z. built and refined the structural models. T.Z. and Y.D. performed the radiolabeled [3H]-thiamine uptake assay. S.P. carried out the [3H]-pyridoxine uptake experiments. Y.W. and Y.D. carried out the thermostability and GFP thermal shift assay. N.C. and C.S. performed the MD simulation studies. C.-H.L. assisted in model building and structural analysis. Z.Z. wrote the manuscript. All authors participated in manuscript preparation and revision.

Corresponding authors

Correspondence to Chia-Hsueh Lee or Zhe Zhang.

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The authors declare no competing interests.

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The original online version of this article was revised: during proofreading, the authors intended to update Fig. S1 in the Supplementary information. They inadvertently uploaded only Fig. S1 without uploading the full supplementary file.

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Dang, Y., Zhang, T., Pidathala, S. et al. Substrate and drug recognition mechanisms of SLC19A3. Cell Res (2024). https://doi.org/10.1038/s41422-024-00951-2

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