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- EMDB-37983: Overall structure of the LAT1-4F2hc bound with Leu -

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Basic information

Entry
Database: EMDB / ID: EMD-37983
TitleOverall structure of the LAT1-4F2hc bound with Leu
Map data
Sample
  • Complex: Overall structure of the LAT1-4F2hc bound with Leu
    • Protein or peptide: Amino acid transporter heavy chain SLC3A2
    • Protein or peptide: Large neutral amino acids transporter small subunit 1
  • Ligand: LEUCINE
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 / external side of apical plasma membrane / neutral L-amino acid transmembrane transporter activity / Tryptophan catabolism / exogenous protein binding / Amino acid transport across the plasma membrane / amino acid transmembrane transporter activity / anchoring junction / antiporter activity / Basigin interactions / xenobiotic transport / response to muscle activity / microvillus membrane / positive regulation of interleukin-4 production / response to exogenous dsRNA / positive regulation of interleukin-17 production / amino acid transport / 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: 3.1 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
DepositionNov 6, 2023-
Header (metadata) releaseNov 13, 2024-
Map releaseNov 13, 2024-
UpdateNov 26, 2025-
Current statusNov 26, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_37983.png

Downloads & links

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Map

FileDownload / File: emd_37983.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.86 Å/pix.
x 288 pix.
= 246.24 Å		0.86 Å/pix.
x 288 pix.
= 246.24 Å		0.86 Å/pix.
x 288 pix.
= 246.24 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.855 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.22
Minimum - Maximum-0.33936322 - 0.8757329
Average (Standard dev.)-0.00079405 (±0.032610152)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 246.24 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_37983_half_map_1.map
Projections & Slices
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Slices (1/2)
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Half map: #1

Fileemd_37983_half_map_2.map
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Sample components

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

EntireName: Overall structure of the LAT1-4F2hc bound with Leu
Components
  • Complex: Overall structure of the LAT1-4F2hc bound with Leu
    • Protein or peptide: Amino acid transporter heavy chain SLC3A2
    • Protein or peptide: Large neutral amino acids transporter small subunit 1
  • Ligand: LEUCINE

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

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

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Macromolecule #1: Amino acid transporter heavy chain SLC3A2

MacromoleculeName: Amino acid transporter heavy chain SLC3A2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 51.854785 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: FTGLSKEELL KVAGSPGWVR TRWALLLLFW LGWLGMLAGA VVIIVRAPRC RELPAQKWWH TGALYRIGDL QAFQGHGAGN LAGLKGRLD YLSSLKVKGL VLGPIHKNQK DDVAQTDLLQ IDPNFGSKED FDSLLQSAKK KSIRVILDLT PNYRGENSWF S TQVDTVAT ...String:
FTGLSKEELL KVAGSPGWVR TRWALLLLFW LGWLGMLAGA VVIIVRAPRC RELPAQKWWH TGALYRIGDL QAFQGHGAGN LAGLKGRLD YLSSLKVKGL VLGPIHKNQK DDVAQTDLLQ IDPNFGSKED FDSLLQSAKK KSIRVILDLT PNYRGENSWF S TQVDTVAT KVKDALEFWL QAGVDGFQVR DIENLKDASS FLAEWQNITK GFSEDRLLIA GTNSSDLQQI LSLLESNKDL LL TSSYLSD SGSTGEHTKS LVTQYLNATG NRWCSWSLSQ ARLLTSFLPA QLLRLYQLML FTLPGTPVFS YGDEIGLDAA ALP GQPMEA PVMLWDESSF PDIPGAVSAN MTVKGQSEDP GSLLSLFRRL SDQRSKERSL LHGDFHAFSA GPGLFSYIRH WDQN ERFLV VLNFGDVGLS AGLQASDLPA SASLPAKADL LLSTQPGREE GSPLELERLK LEPHEGLLLR FPYAA

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: 50.81909 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: VTLQRNITLL NGVAIIVGTI IGSGIFVTPT GVLKEAGSPG LALVVWAACG VFSIVGALCY AELGTTISKS GGDYAYMLEV YGSLPAFLK LWIELLIIRP SSQYIVALVF ATYLLKPLFP TCPVPEEAAK LVACLCVLLL TAVNCYSVKA ATRVQDAFAA A KLLALALI ...String:
VTLQRNITLL NGVAIIVGTI IGSGIFVTPT GVLKEAGSPG LALVVWAACG VFSIVGALCY AELGTTISKS GGDYAYMLEV YGSLPAFLK LWIELLIIRP SSQYIVALVF ATYLLKPLFP TCPVPEEAAK LVACLCVLLL TAVNCYSVKA ATRVQDAFAA A KLLALALI ILLGFVQIGK GDVSNLDPNF SFEGTKLDVG NIVLALYSGL FAYGGWNYLN FVTEEMINPY RNLPLAIIIS LP IVTLVYV LTNLAYFTTL STEQMLSSEA VAVDFGNYHL GVMSWIIPVF VGLSCFGSVN GSLFTSSRLF FVGSREGHLP SIL SMIHPQ LLTPVPSLVF TCVMTLLYAF SKDIFSVINF FSFFNWLCVA LAIIGMIWLR HRKPELERPI KVNLALPVFF ILAC LFLIA VSFWKTPVEC GIGFTIILSG LPVYFFGVWW KNKPKWLLQG IFSTTVLCQK LMQVVPQET

UniProtKB: Large neutral amino acids transporter small subunit 1

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Macromolecule #4: LEUCINE

MacromoleculeName: LEUCINE / type: ligand / ID: 4 / Number of copies: 1 / Formula: LEU
Molecular weightTheoretical: 131.173 Da
Chemical component information

ChemComp-LEU:
LEUCINE

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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: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 596542
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER

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