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- PDB-8kdn: Structure of LAT1-CD98hc in complex with L-Phe, focused on TMD -

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Basic information

Entry
Database: PDB / ID: 8kdn
TitleStructure of LAT1-CD98hc in complex with L-Phe, focused on TMD
Components
  • 4F2 cell-surface antigen heavy chain
  • Large neutral amino acids transporter small subunit 1
KeywordsTRANSPORT PROTEIN / Transporter / Amino acid / Complex / Cancer
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 / alanine transport / proline 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 / amino acid import across plasma membrane / positive regulation of cytokine production involved in immune response / 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 / antiporter activity / anchoring junction / Basigin interactions / xenobiotic transport / microvillus membrane / response to muscle activity / 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
PHENYLALANINE / Amino acid transporter heavy chain SLC3A2 / Large neutral amino acids transporter small subunit 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.12 Å
AuthorsLee, Y.
Funding support Germany, 1items
OrganizationGrant numberCountry
Max Planck Society Germany
CitationJournal: Nat Commun / Year: 2025
Title: Structural basis of anticancer drug recognition and amino acid transport by LAT1.
Authors: Yongchan Lee / Chunhuan Jin / Ryuichi Ohgaki / Minhui Xu / Satoshi Ogasawara / Rangana Warshamanage / Keitaro Yamashita / Garib Murshudov / Osamu Nureki / Takeshi Murata / Yoshikatsu Kanai /
Abstract: LAT1 (SLC7A5) transports large neutral amino acids and plays pivotal roles in cancer proliferation, immune response and drug delivery. Despite recent advances in structural understanding of LAT1, how ...LAT1 (SLC7A5) transports large neutral amino acids and plays pivotal roles in cancer proliferation, immune response and drug delivery. Despite recent advances in structural understanding of LAT1, how it discriminates substrates and inhibitors including the clinically relevant drugs remains elusive. Here we report six structures of LAT1 across three conformations with bound ligands, elucidating its substrate transport and inhibitory mechanisms. JPH203 (also known as nanvuranlat or KYT-0353), an anticancer drug in clinical trials, traps LAT1 in an outward-facing state with a U-shaped conformer, with its amino-phenylbenzoxazol moiety pushing against transmembrane helix 3 (TM3) and bending TM10. Physiological substrates like ʟ-Phe lack such effects, whereas melphalan poses steric hindrance, explaining its inhibitory activity. The "classical" system L inhibitor BCH induces an occluded state critical for transport, confirming its substrate-like behavior. These findings provide a structural basis for substrate recognition and inhibition of LAT1, guiding future drug design.
History
DepositionAug 9, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 12, 2025Provider: repository / Type: Initial release
Revision 1.0Feb 12, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Feb 12, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
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Revision 1.1Feb 26, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 4F2 cell-surface antigen heavy chain
B: Large neutral amino acids transporter small subunit 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)124,2793
Polymers124,1132
Non-polymers1651
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 4F2 cell-surface antigen heavy chain / Glycoprotein / 4F2hc / 4F2 heavy chain antigen / Lymphocyte activation antigen 4F2 large subunit / ...Glycoprotein / 4F2hc / 4F2 heavy chain antigen / Lymphocyte activation antigen 4F2 large subunit / Solute carrier family 3 member 2


Mass: 68069.625 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC3A2, MDU1 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P08195
#2: Protein Large neutral amino acids transporter small subunit 1 / 4F2 light chain / 4F2LC / CD98 light chain / Integral membrane protein E16 / L-type amino acid ...4F2 light chain / 4F2LC / CD98 light chain / Integral membrane protein E16 / L-type amino acid transporter 1 / hLAT1 / Solute carrier family 7 member 5 / y+ system cationic amino acid transporter


Mass: 56043.746 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC7A5, CD98LC, LAT1, MPE16 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q01650
#3: Chemical ChemComp-PHE / PHENYLALANINE


Type: L-peptide linking / Mass: 165.189 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H11NO2 / Feature type: SUBJECT OF INVESTIGATION
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: LAT1-CD98hc-Fab170 / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightValue: 0.173 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
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: TFS 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: 800 nm
Image recordingElectron dose: 51 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4.12 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 174905 / Symmetry type: POINT
RefinementResolution: 4.12→4.12 Å / Cor.coef. Fo:Fc: 0.932 / SU B: 20.057 / SU ML: 0.28 / ESU R: 0.923
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflection
Rwork0.32522 --
obs0.32522 23142 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 239.923 Å2
Refinement stepCycle: 1 / Total: 3930
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.010.0114034
ELECTRON MICROSCOPYr_bond_other_d00.0164026
ELECTRON MICROSCOPYr_angle_refined_deg1.8921.6245507
ELECTRON MICROSCOPYr_angle_other_deg0.6391.5549224
ELECTRON MICROSCOPYr_dihedral_angle_1_deg8.1775503
ELECTRON MICROSCOPYr_dihedral_angle_2_deg8.617514
ELECTRON MICROSCOPYr_dihedral_angle_3_deg14.85210652
ELECTRON MICROSCOPYr_dihedral_angle_4_deg
ELECTRON MICROSCOPYr_chiral_restr0.0870.2665
ELECTRON MICROSCOPYr_gen_planes_refined0.0040.024564
ELECTRON MICROSCOPYr_gen_planes_other0.0010.02924
ELECTRON MICROSCOPYr_nbd_refined
ELECTRON MICROSCOPYr_nbd_other
ELECTRON MICROSCOPYr_nbtor_refined
ELECTRON MICROSCOPYr_nbtor_other
ELECTRON MICROSCOPYr_xyhbond_nbd_refined
ELECTRON MICROSCOPYr_xyhbond_nbd_other
ELECTRON MICROSCOPYr_metal_ion_refined
ELECTRON MICROSCOPYr_metal_ion_other
ELECTRON MICROSCOPYr_symmetry_vdw_refined
ELECTRON MICROSCOPYr_symmetry_vdw_other
ELECTRON MICROSCOPYr_symmetry_hbond_refined
ELECTRON MICROSCOPYr_symmetry_hbond_other
ELECTRON MICROSCOPYr_symmetry_metal_ion_refined
ELECTRON MICROSCOPYr_symmetry_metal_ion_other
ELECTRON MICROSCOPYr_mcbond_it41.48420.6192024
ELECTRON MICROSCOPYr_mcbond_other41.42220.622024
ELECTRON MICROSCOPYr_mcangle_it55.69137.2332523
ELECTRON MICROSCOPYr_mcangle_other55.68437.2312524
ELECTRON MICROSCOPYr_scbond_it49.60325.7862010
ELECTRON MICROSCOPYr_scbond_other49.58625.7822010
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other73.04245.3852985
ELECTRON MICROSCOPYr_long_range_B_refined74.254255.6816371
ELECTRON MICROSCOPYr_long_range_B_other74.252255.6716372
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 3.9→4.001 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork1.283 1708 -
obs--100 %

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