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

Yongchan Lee (yongchan.lee@biophys.mpg.de), Chunhuan Jin, Ryuichi Ohgaki, Minhui Xu, Satoshi Ogasawara, Rangana Warshamanage, Keitaro Yamashita, Garib Murshudov, Osamu Nureki, Takeshi Murata and Yoshikatsu Kanai (ykanai@pharma1.med.osaka-u.ac.jp)
Additional contact information
Yongchan Lee: Max Planck Institute of Biophysics
Chunhuan Jin: Osaka University
Ryuichi Ohgaki: 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

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: 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.

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-56903-w Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56903-w

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-56903-w

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla (sonal.shukla@springer.com) and Springer Nature Abstracting and Indexing (indexing@springernature.com).