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- EMDB-35361: Overall structure of the LAT1-4F2hc bound with tyrosine -

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Basic information

Entry
Database: EMDB / ID: EMD-35361
TitleOverall structure of the LAT1-4F2hc bound with tyrosine
Map data
Sample
  • Complex: Overall structure of the LAT1-4F2hc bound with tyrosine
    • Protein or peptide: 4F2 cell-surface antigen heavy chain
    • Protein or peptide: Large neutral amino acids transporter small subunit 1
  • Ligand: TYROSINE
Keywordscomplex / membrane protein / amino acid
Function / homology
Function and homology information


L-tryptophan transmembrane transport / positive regulation of L-leucine import across plasma membrane / L-tryptophan transmembrane transporter activity / cellular response to L-arginine / apical pole of neuron / tyrosine transport / L-histidine transport / amino acid transport complex / L-leucine import across plasma membrane / L-alanine transmembrane transporter activity ...L-tryptophan transmembrane transport / positive regulation of L-leucine import across plasma membrane / L-tryptophan transmembrane transporter activity / cellular response to L-arginine / apical pole of neuron / tyrosine transport / L-histidine transport / amino acid transport complex / L-leucine import across plasma membrane / L-alanine transmembrane transporter activity / L-alanine import across plasma membrane / Defective SLC7A7 causes lysinuric protein intolerance (LPI) / aromatic amino acid transmembrane transporter activity / phenylalanine transport / methionine transport / L-leucine transmembrane transporter activity / amino acid transmembrane transport / thyroid hormone transmembrane transporter activity / isoleucine transport / valine transport / proline transport / alanine transport / L-amino acid transmembrane transporter activity / L-leucine transport / thyroid hormone transport / negative regulation of vascular associated smooth muscle cell apoptotic process / neutral amino acid transport / positive regulation of cytokine production involved in immune response / amino acid import across plasma membrane / neutral L-amino acid transmembrane transporter activity / external side of apical plasma membrane / Tryptophan catabolism / Amino acid transport across the plasma membrane / amino acid transmembrane transporter activity / exogenous protein binding / anchoring junction / antiporter activity / Basigin interactions / xenobiotic transport / response to muscle activity / microvillus membrane / positive regulation of interleukin-4 production / response to exogenous dsRNA / amino acid transport / positive regulation of interleukin-17 production / tryptophan transport / positive regulation of glial cell proliferation / response to hyperoxia / transport across blood-brain barrier / cellular response to glucose starvation / liver regeneration / negative regulation of autophagy / basal plasma membrane / peptide antigen binding / positive regulation of type II interferon production / calcium ion transport / melanosome / double-stranded RNA binding / cellular response to lipopolysaccharide / virus receptor activity / basolateral plasma membrane / carbohydrate metabolic process / apical plasma membrane / cadherin binding / protein heterodimerization activity / negative regulation of gene expression / lysosomal membrane / intracellular membrane-bounded organelle / synapse / symbiont entry into host cell / cell surface / protein homodimerization activity / RNA binding / extracellular exosome / nucleoplasm / membrane / plasma membrane / cytosol
Similarity search - Function
L-type amino acid transporter / Solute carrier family 3 member 2, N-terminal domain / 4F2 cell-surface antigen heavy chain / Solute carrier family 3 member 2 N-terminus / : / Amino acid/polyamine transporter I / Amino acid permease / Alpha amylase, catalytic domain / Glycosyl hydrolase, family 13, catalytic domain / Alpha-amylase domain ...L-type amino acid transporter / Solute carrier family 3 member 2, N-terminal domain / 4F2 cell-surface antigen heavy chain / Solute carrier family 3 member 2 N-terminus / : / Amino acid/polyamine transporter I / Amino acid permease / Alpha amylase, catalytic domain / Glycosyl hydrolase, family 13, catalytic domain / Alpha-amylase domain / Glycosyl hydrolase, all-beta / Glycoside hydrolase superfamily
Similarity search - Domain/homology
Amino acid transporter heavy chain SLC3A2 / Large neutral amino acids transporter small subunit 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsYan RH / Li YN / Shi TH
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: J Biol Chem / Year: 2025
Title: Structural insights into the substrate transport mechanism of the amino acid transporter complex.
Authors: Haonan Yang / Tianhao Shi / Jing Dong / Ting Zhang / Yaning Li / Yingying Guo / Yafei Yuan / Liuqing Yang / Jin-Tang Dong / Renhong Yan /
Abstract: The -type amino acid transporter 1 (LAT1), in complex with its ancillary protein 4F2hc, mediates the sodium-independent antiport of large neutral amino acids across the plasma membrane. LAT1 ...The -type amino acid transporter 1 (LAT1), in complex with its ancillary protein 4F2hc, mediates the sodium-independent antiport of large neutral amino acids across the plasma membrane. LAT1 preferentially transports substrates, such as -leucine, -tyrosine, and -tryptophan, thyroid hormones, and drugs like 3,4-dihydroxyphenylalanine. Its pivotal role in cancer development and progression has established LAT1 as a promising therapeutic target. While prior studies have resolved the LAT1-4F2hc architecture and inhibitor interactions, the molecular basis of LAT1 substrate selectivity remains elusive. Here, we present the cryo-EM structures of LAT1-4F2hc bound to -tyrosine, -tryptophan, -leucine, and 3,4-dihydroxyphenylalanine, revealing distinct substrate binding modes. Comparative structural analysis highlights differences between LAT1 and LAT2 in substrate coordination, driven by key residues near the binding pocket that influence transport efficiency. These findings advance our mechanistic understanding of the LAT1-4F2hc complex and provide valuable insights for structure-based drug design targeting LAT1.
History
DepositionFeb 12, 2023-
Header (metadata) releaseJul 10, 2024-
Map releaseJul 10, 2024-
UpdateNov 26, 2025-
Current statusNov 26, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_35361.png

Downloads & links

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Map

FileDownload / File: emd_35361.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
1.09 Å/pix.
x 256 pix.
= 278.272 Å		1.09 Å/pix.
x 256 pix.
= 278.272 Å		1.09 Å/pix.
x 256 pix.
= 278.272 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.087 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0265
Minimum - Maximum-0.08487881 - 0.1605643
Average (Standard dev.)-0.00013615054 (±0.0035962737)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 278.272 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_35361_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_35361_half_map_2.map
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Sample components

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Entire : Overall structure of the LAT1-4F2hc bound with tyrosine

EntireName: Overall structure of the LAT1-4F2hc bound with tyrosine
Components
  • Complex: Overall structure of the LAT1-4F2hc bound with tyrosine
    • Protein or peptide: 4F2 cell-surface antigen heavy chain
    • Protein or peptide: Large neutral amino acids transporter small subunit 1
  • Ligand: TYROSINE

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Supramolecule #1: Overall structure of the LAT1-4F2hc bound with tyrosine

SupramoleculeName: Overall structure of the LAT1-4F2hc bound with tyrosine
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: 4F2 cell-surface antigen heavy chain

MacromoleculeName: 4F2 cell-surface antigen heavy chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 70.160828 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAHHHHHHHH HHSGRELQPP EASIAVVSIP RQLPGSHSEA GVQGLSAGDD SETGSDCVTQ AGLQLLASSD PPALASKNAE VTVETGFHH VSQADIEFLT SIDPTASASG SAGITGTMSQ DTEVDMKEVE LNELEPEKQP MNAASGAAMS LAGAEKNGLV K IKVAEDEA ...String:
MAHHHHHHHH HHSGRELQPP EASIAVVSIP RQLPGSHSEA GVQGLSAGDD SETGSDCVTQ AGLQLLASSD PPALASKNAE VTVETGFHH VSQADIEFLT SIDPTASASG SAGITGTMSQ DTEVDMKEVE LNELEPEKQP MNAASGAAMS LAGAEKNGLV K IKVAEDEA EAAAAAKFTG LSKEELLKVA GSPGWVRTRW ALLLLFWLGW LGMLAGAVVI IVRAPRCREL PAQKWWHTGA LY RIGDLQA FQGHGAGNLA GLKGRLDYLS SLKVKGLVLG PIHKNQKDDV AQTDLLQIDP NFGSKEDFDS LLQSAKKKSI RVI LDLTPN YRGENSWFST QVDTVATKVK DALEFWLQAG VDGFQVRDIE NLKDASSFLA EWQNITKGFS EDRLLIAGTN SSDL QQILS LLESNKDLLL TSSYLSDSGS TGEHTKSLVT QYLNATGNRW CSWSLSQARL LTSFLPAQLL RLYQLMLFTL PGTPV FSYG DEIGLDAAAL PGQPMEAPVM LWDESSFPDI PGAVSANMTV KGQSEDPGSL LSLFRRLSDQ RSKERSLLHG DFHAFS AGP GLFSYIRHWD QNERFLVVLN FGDVGLSAGL QASDLPASAS LPAKADLLLS TQPGREEGSP LELERLKLEP HEGLLLR FP YAALE

UniProtKB: Amino acid transporter heavy chain SLC3A2

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Macromolecule #2: Large neutral amino acids transporter small subunit 1

MacromoleculeName: Large neutral amino acids transporter small subunit 1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 57.186895 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MADYKDDDDK SGPDEVDASG RAGAGPKRRA LAAPAAEEKE EAREKMLAAK SADGSAPAGE GEGVTLQRNI TLLNGVAIIV GTIIGSGIF VTPTGVLKEA GSPGLALVVW AACGVFSIVG ALCYAELGTT ISKSGGDYAY MLEVYGSLPA FLKLWIELLI I RPSSQYIV ...String:
MADYKDDDDK SGPDEVDASG RAGAGPKRRA LAAPAAEEKE EAREKMLAAK SADGSAPAGE GEGVTLQRNI TLLNGVAIIV GTIIGSGIF VTPTGVLKEA GSPGLALVVW AACGVFSIVG ALCYAELGTT ISKSGGDYAY MLEVYGSLPA FLKLWIELLI I RPSSQYIV ALVFATYLLK PLFPTCPVPE EAAKLVACLC VLLLTAVNCY SVKAATRVQD AFAAAKLLAL ALIILLGFVQ IG KGDVSNL DPNFSFEGTK LDVGNIVLAL YSGLFAYGGW NYLNFVTEEM INPYRNLPLA IIISLPIVTL VYVLTNLAYF TTL STEQML SSEAVAVDFG NYHLGVMSWI IPVFVGLSCF GSVNGSLFTS SRLFFVGSRE GHLPSILSMI HPQLLTPVPS LVFT CVMTL LYAFSKDIFS VINFFSFFNW LCVALAIIGM IWLRHRKPEL ERPIKVNLAL PVFFILACLF LIAVSFWKTP VECGI GFTI ILSGLPVYFF GVWWKNKPKW LLQGIFSTTV LCQKLMQVVP QET

UniProtKB: Large neutral amino acids transporter small subunit 1

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Macromolecule #4: TYROSINE

MacromoleculeName: TYROSINE / type: ligand / ID: 4 / Number of copies: 1 / Formula: TYR
Molecular weightTheoretical: 181.189 Da
Chemical component information

ChemComp-TYR:
TYROSINE

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 5.0 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7dsq

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: OTHER / Number images used: 170888
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER

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