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Molecular basis of SLC19A1-mediated folate and cyclic dinucleotide transport

Author

Listed:
  • Qixiang Zhang

    (Beijing Institute of Technology)

  • Xuyuan Zhang

    (Chinese Academy of Sciences)

  • Kexin Liu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Yalan Zhu

    (Beijing Institute of Technology)

  • Xiaohua Nie

    (Chinese Academy of Sciences)

  • Junxiao Ma

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Panpan Sun

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Zhaolong Li

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Yina Gao

    (Chinese Academy of Sciences)

  • Songqing Liu

    (Chinese Academy of Sciences)

  • Ang Gao

    (Beijing Institute of Technology
    Shandong Academy of Medical Sciences)

  • Liguo Zhang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Pu Gao

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Shandong Academy of Medical Sciences)

Abstract

The solute carrier protein SLC19A1 is crucial for transporting folate nutrients, antifolate chemotherapeutics, and more recently cyclic dinucleotides (CDNs) immune transmitters, influencing various physiological and pathological processes. While the inward-open state of human SLC19A1 (hSLC19A1) has been previously described, key aspects regarding its conformational dynamics, substrate selectivity, and precise mechanisms underlying CDNs transport remain elusive. Using an antibody-facilitated conformation screening strategy, we present cryo-electron microscopy structures of hSLC19A1 in its outward-open state with and without bound substrates, revealing detailed mechanisms of substrate recognition and conformational changes during transport. We identify both general and specific features for folate/antifolate recognition, including an SLC19A1-specific pocket for accommodating γ-carboxylate-modified antifolates. Intriguingly, CDNs bind as monomers within the canonical pocket of outward-open hSLC19A1, contrasting with dimeric binding in inward-open structures. Together with functional assays, these findings provide a framework for developing antifolate drugs and CDN-targeted therapies, advancing our understanding of SLC19A1’s physiological and therapeutic functions.

Suggested Citation

  • Qixiang Zhang & Xuyuan Zhang & Kexin Liu & Yalan Zhu & Xiaohua Nie & Junxiao Ma & Panpan Sun & Zhaolong Li & Yina Gao & Songqing Liu & Ang Gao & Liguo Zhang & Pu Gao, 2025. "Molecular basis of SLC19A1-mediated folate and cyclic dinucleotide transport," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58378-1
    DOI: 10.1038/s41467-025-58378-1
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    References listed on IDEAS

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    1. Joanne L. Parker & Justin C. Deme & Gabriel Kuteyi & Zhiyi Wu & Jiandong Huo & I. David Goldman & Raymond J. Owens & Philip C. Biggin & Susan M. Lea & Simon Newstead, 2021. "Structural basis of antifolate recognition and transport by PCFT," Nature, Nature, vol. 595(7865), pages 130-134, July.
    2. Dara L. Burdette & Kathryn M. Monroe & Katia Sotelo-Troha & Jeff S. Iwig & Barbara Eckert & Mamoru Hyodo & Yoshihiro Hayakawa & Russell E. Vance, 2011. "STING is a direct innate immune sensor of cyclic di-GMP," Nature, Nature, vol. 478(7370), pages 515-518, October.
    3. Guijun Shang & Conggang Zhang & Zhijian J. Chen & Xiao-chen Bai & Xuewu Zhang, 2019. "Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP–AMP," Nature, Nature, vol. 567(7748), pages 389-393, March.
    4. Larry H. Matherly & Zhanjun Hou, 2022. "Folate transporter offers clues for anticancer drugs," Nature, Nature, vol. 612(7938), pages 39-41, December.
    5. Nicholas J. Wright & Justin G. Fedor & Han Zhang & Pyeonghwa Jeong & Yang Suo & Jiho Yoo & Jiyong Hong & Wonpil Im & Seok-Yong Lee, 2022. "Methotrexate recognition by the human reduced folate carrier SLC19A1," Nature, Nature, vol. 609(7929), pages 1056-1062, September.
    6. Qixiang Zhang & Xuyuan Zhang & Yalan Zhu & Panpan Sun & Liwei Zhang & Junxiao Ma & Yong Zhang & Lingan Zeng & Xiaohua Nie & Yina Gao & Zhaolong Li & Songqing Liu & Jizhong Lou & Ang Gao & Liguo Zhang , 2022. "Recognition of cyclic dinucleotides and folates by human SLC19A1," Nature, Nature, vol. 612(7938), pages 170-176, December.
    7. Nan Wang & Shuo Zhang & Yafei Yuan & Hanwen Xu & Elisabeth Defossa & Hans Matter & Melissa Besenius & Volker Derdau & Matthias Dreyer & Nis Halland & Kaihui Hu He & Stefan Petry & Michael Podeschwa & , 2022. "Molecular basis for inhibiting human glucose transporters by exofacial inhibitors," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
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