8KDG

Structure of LAT1-CD98hc-Fab170 in complex with BCH, consensus map

8KDG の概要

• エントリーDOI: 10.2210/pdb8kdg/pdb
• EMDBエントリー: 37135
• 分子名称: 4F2 cell-surface antigen heavy chain, Large neutral amino acids transporter small subunit 1, Fab170 light chain, ... (6 entities in total)
• 機能のキーワード: transporter, amino acid, complex, cancer, transport protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 174491.29

構造登録者

Lee, Y. (登録日: 2023-08-09, 公開日: 2025-02-12, 最終更新日: 2025-02-26)

主引用文献

Lee, Y.,Jin, C.,Ohgaki, R.,Xu, M.,Ogasawara, S.,Warshamanage, R.,Yamashita, K.,Murshudov, G.,Nureki, O.,Murata, T.,Kanai, Y.
Structural basis of anticancer drug recognition and amino acid transport by LAT1.
Nat Commun, 16:1635-1635, 2025

PubMed 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.

PubMed: 39952931
DOI: 10.1038/s41467-025-56903-w

実験手法

ELECTRON MICROSCOPY (3.68 Å)