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- PDB-9jbu: Structure of LAT4 in complex with digitonin -

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Basic information

Entry
Database: PDB / ID: 9jbu
TitleStructure of LAT4 in complex with digitonin
ComponentsLarge neutral amino acids transporter small subunit 4
KeywordsMEMBRANE PROTEIN / LAT4 / SLC43A2 / amino acid transporter
Function / homology
Function and homology information


negative regulation of amino acid transport / negative regulation of L-leucine import across plasma membrane / L-phenylalanine transmembrane transporter activity / L-methionine transmembrane transporter activity / L-isoleucine transmembrane transporter activity / phenylalanine transport / methionine transport / L-leucine transmembrane transporter activity / isoleucine transport / L-amino acid transmembrane transporter activity ...negative regulation of amino acid transport / negative regulation of L-leucine import across plasma membrane / L-phenylalanine transmembrane transporter activity / L-methionine transmembrane transporter activity / L-isoleucine transmembrane transporter activity / phenylalanine transport / methionine transport / L-leucine transmembrane transporter activity / isoleucine transport / L-amino acid transmembrane transporter activity / L-leucine transport / neutral amino acid transport / neutral L-amino acid transmembrane transporter activity / Amino acid transport across the plasma membrane / amino acid transmembrane transporter activity / amino acid transport / basolateral plasma membrane / plasma membrane
Similarity search - Function
Major facilitator superfamily / Major Facilitator Superfamily / MFS transporter superfamily
Similarity search - Domain/homology
Large neutral amino acids transporter small subunit 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsYin, Y.X. / Ding, D. / Lu, Y.S. / Chen, H.Y.
Funding support China, 3items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82030081 China
National Natural Science Foundation of China (NSFC)81874235 China
National Natural Science Foundation of China (NSFC)82173386 China
CitationJournal: EMBO J / Year: 2026
Title: Structures of the neutral amino acid transporter LAT4 provide insights into antitumor effects of its inhibitor tubeimoside-1.
Authors: Dian Ding / Yishuo Lu / Jingyi Yang / Hongyi Chen / Peijun Jiang / Yan Jin / Jianyuan Luo / Guangxi Wang / Yuxin Yin /
Abstract: 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 ...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.
History
DepositionAug 27, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Mar 11, 2026Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Large neutral amino acids transporter small subunit 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,0272
Polymers62,7981
Non-polymers1,2291
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Large neutral amino acids transporter small subunit 4 / L-type amino acid transporter 4 / Solute carrier family 43 member 2


Mass: 62797.562 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC43A2, LAT4, PP7664 / Production host: Homo sapiens (human) / References: UniProt: Q8N370
#2: Chemical ChemComp-AJP / Digitonin


Mass: 1229.312 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C56H92O29 / Feature type: SUBJECT OF INVESTIGATION / Comment: detergent*YM
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Large neutral amino acids transporter small subunit 4 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 56 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: cryoSPARC / Category: 3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 177241 / Symmetry type: POINT

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