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TitleStructures of the neutral amino acid transporter LAT4 provide insights into antitumor effects of its inhibitor tubeimoside-1.
Journal, issue, pagesEMBO J, Vol. 45, Issue 12, Page 4283-4298, Year 2026
Publish dateMay 4, 2026
AuthorsDian Ding / Yishuo Lu / Jingyi Yang / Hongyi Chen / Peijun Jiang / Yan Jin / Jianyuan Luo / Guangxi Wang / Yuxin Yin /
PubMed AbstractMethionine restriction has emerged as a promising strategy for extending lifespan and enhancing cancer therapy. LAT4, an amino acid transporter encoded by SLC43A2, is frequently overexpressed in ...Methionine restriction has emerged as a promising strategy for extending lifespan and enhancing cancer therapy. LAT4, an amino acid transporter encoded by SLC43A2, is frequently overexpressed in multiple cancers and critically contributes to systemic methionine accumulation. However, the structural basis of LAT4 function remains poorly understood, and no effective inhibitors have been developed to date. In this study, we present high-resolution cryo-electron microscopy structures of LAT4 and the related SLC43A3-encoded purine transporter ENBT1. The phenylalanine-bound structure of LAT4 enables the characterization of the substrate binding pocket. Comparison of the outward-facing ENBT1 and inward-facing LAT4 structures identifies key residues involved in the methionine transport process. Structural analysis of digitonin binding to the central cavity of LAT4 enabled identification of tubeimoside-1 (TBM-1) as a potent inhibitor of LAT4-mediated methionine uptake. We demonstrate that tubeimoside-1 reduces methionine uptake in B16F10 cancer cells. Furthermore, TBM-1 suppresses tumor progression in the MMTV-PyVT mouse model of breast cancer through systemic methionine restriction. Our study provides insights into the LAT4 transport mechanism and identifies tubeimoside-1 as a potent inhibitor of methionine uptake and establishes a foundation for developing LAT4-targeting therapeutics to restrict methionine uptake.
External linksEMBO J / PubMed:42082777 / PubMed Central
MethodsEM (single particle)
Resolution2.88 - 3.8 Å
Structure data

61324

9jbs

EMDB-61324, PDB-9jbs:
Structure of LAT4 in the apo state
Method: EM (single particle) / Resolution: 2.88 Å

61325

9jbt

EMDB-61325, PDB-9jbt:
Structure of LAT4 in complex with Phe
Method: EM (single particle) / Resolution: 3.2 Å

61326

9jbu

EMDB-61326, PDB-9jbu:
Structure of LAT4 in complex with digitonin
Method: EM (single particle) / Resolution: 3.8 Å

62783

9l38

EMDB-62783, PDB-9l38:
Structure of ENBT1 in the apo state
Method: EM (single particle) / Resolution: 3.2 Å

Chemicals

ChemComp-PHE:
PHENYLALANINE

ChemComp-AJP:
Digitonin / detergent*YM

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / LAT4 / SLC43A2 / amino acid transporter / ENBT1 / SLC43A3

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