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Nat. Commun., Published: 14 February 2025 | https://doi.org/10.1038/s41467-025-56903-w
Structural basis of anticancer drug recognition and amino acid transport by LAT1
Yongchan Lee1,2, Chunhuan Jin3, Ryuichi Ohgaki3,4, Minhui Xu3, Satoshi Ogasawara5, Rangana Warshamanage6, Keitaro Yamashita7, Garib Murshudov7, Osamu Nureki8, Takeshi Murata5 &Yoshikatsu Kanai3,4,9
1Department of Structural Biology, Max Planck Institute of Biophysics, 60438 Frankfurt, Germany.
2Graduate School of Medical Life Science, Yokohama City University, Yokohama, Kanagawa 230-0045, Japan.
3Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
4Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka 565-0871, Japan.
5Graduate School of Science, Chiba University, Chiba 263-8522, Japan.
6Scientific Computing Department, UKRI Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Campus, Didcot OX11 0FA, UK.
7Structural Studies Division, MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
8Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan.
9Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe), Osaka University, Osaka 565-0871, Japan.
Corresponding authors
Correspondence to Yongchan Lee or Yoshikatsu Kanai.
1Department of Structural Biology, Max Planck Institute of Biophysics, 60438 Frankfurt, Germany.
2Graduate School of Medical Life Science, Yokohama City University, Yokohama, Kanagawa 230-0045, Japan.
3Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
4Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka 565-0871, Japan.
5Graduate School of Science, Chiba University, Chiba 263-8522, Japan.
6Scientific Computing Department, UKRI Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Campus, Didcot OX11 0FA, UK.
7Structural Studies Division, MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
8Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan.
9Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe), Osaka University, Osaka 565-0871, Japan.
Corresponding authors
Correspondence to Yongchan Lee or Yoshikatsu Kanai.
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.
논문정보
- Research article
- 2025년 02월 (BRIC 등록일 2025-02-27)
- 국외 연구진
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