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Structural basis of anticancer drug recognition and amino acid transport by LAT1

Author

Listed:
  • Yongchan Lee

    (Max Planck Institute of Biophysics
    Yokohama City University)

  • Chunhuan Jin

    (Osaka University)

  • Ryuichi Ohgaki

    (Osaka University
    Osaka University)

  • Minhui Xu

    (Osaka University)

  • Satoshi Ogasawara

    (Chiba University)

  • Rangana Warshamanage

    (Harwell Campus)

  • Keitaro Yamashita

    (MRC Laboratory of Molecular Biology)

  • Garib Murshudov

    (MRC Laboratory of Molecular Biology)

  • Osamu Nureki

    (The University of Tokyo)

  • Takeshi Murata

    (Chiba University)

  • Yoshikatsu Kanai

    (Osaka University
    Osaka University
    Osaka University)

Abstract

LAT1 (SLC7A5) transports large neutral amino acids and plays pivotal roles in cancer proliferation, immune response and drug delivery. Despite recent advances in structural understanding of LAT1, how it discriminates substrates and inhibitors including the clinically relevant drugs remains elusive. Here we report six structures of LAT1 across three conformations with bound ligands, elucidating its substrate transport and inhibitory mechanisms. JPH203 (also known as nanvuranlat or KYT-0353), an anticancer drug in clinical trials, traps LAT1 in an outward-facing state with a U-shaped conformer, with its amino-phenylbenzoxazol moiety pushing against transmembrane helix 3 (TM3) and bending TM10. Physiological substrates like ʟ-Phe lack such effects, whereas melphalan poses steric hindrance, explaining its inhibitory activity. The “classical” system L inhibitor BCH induces an occluded state critical for transport, confirming its substrate-like behavior. These findings provide a structural basis for substrate recognition and inhibition of LAT1, guiding future drug design.

Suggested Citation

  • Yongchan Lee & Chunhuan Jin & Ryuichi Ohgaki & Minhui Xu & Satoshi Ogasawara & Rangana Warshamanage & Keitaro Yamashita & Garib Murshudov & Osamu Nureki & Takeshi Murata & Yoshikatsu Kanai, 2025. "Structural basis of anticancer drug recognition and amino acid transport by LAT1," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56903-w
    DOI: 10.1038/s41467-025-56903-w
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    References listed on IDEAS

    as
    1. Renhong Yan & Xin Zhao & Jianlin Lei & Qiang Zhou, 2019. "Structure of the human LAT1–4F2hc heteromeric amino acid transporter complex," Nature, Nature, vol. 568(7750), pages 127-130, April.
    2. Di Wu & Renhong Yan & Siyuan Song & Andrew K. Swansiger & Yaning Li & James S. Prell & Qiang Zhou & Carol V. Robinson, 2024. "The complete assembly of human LAT1-4F2hc complex provides insights into its regulation, function and localisation," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    3. Tomoya Hino & Takatoshi Arakawa & Hiroko Iwanari & Takami Yurugi-Kobayashi & Chiyo Ikeda-Suno & Yoshiko Nakada-Nakura & Osamu Kusano-Arai & Simone Weyand & Tatsuro Shimamura & Norimichi Nomura & Alexa, 2012. "G-protein-coupled receptor inactivation by an allosteric inverse-agonist antibody," Nature, Nature, vol. 482(7384), pages 237-240, February.
    4. Gregory Gauthier-Coles & Jade Vennitti & Zhiduo Zhang & William C. Comb & Shuran Xing & Kiran Javed & Angelika Bröer & Stefan Bröer, 2021. "Quantitative modelling of amino acid transport and homeostasis in mammalian cells," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
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