Structural and functional elucidation of L-type amino acid transporter under lipid environment

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K15031
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 43020:Structural biochemistry-related
• Research Institution: Yokohama City University
• Principal Investigator: Lee Yongchan 横浜市立大学, 生命医科学研究科, 助教 (00894932)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: アミノ酸輸送体 / クライオ電子顕微鏡 / ナノディスク

Outline of Final Research Achievements

L-type amino acid transporter 1 (LAT1) is a neutral amino acid transporter expressed in the blood-brain barrier and many types of cancer cells and is involved in the transport of hormones and anticancer drugs across the cell membrane. We performed electron cryo-microscopy analyses of LAT1 using the membrane mimetic environment called nanodisc to understand the substrate and drug binding modes. By preparing transporter-ligand complexes with various substrates and inhibitors and performing high-resolution single-particle analyses, we determined the structures of LAT1 in complex with selective and non-selective inhibitors. These results shed light on the structural basis of how anticancer compounds bind to and inhibit LAT1.

Free Research Field

構造生物学

Academic Significance and Societal Importance of the Research Achievements

本研究では、界面活性剤下あるいは脂質環境下で得られるLAT1の構造、とくに阻害薬の結合の挙動に大きな違いがあることが明らかとなった。これは、ここ数年で報告された膜輸送体構造全般の再解釈を促す重要な発見といえる。本研究で得られた阻害薬の作動機構に関する知見は、LAT1を標的とする薬剤候補の改良に役立つことが期待される。