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- PDB-8kdf: Structure of LAT1-CD98hc in complex with JPH203, focused on TMD -

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Basic information

Entry
Database: PDB / ID: 8kdf
TitleStructure of LAT1-CD98hc in complex with JPH203, 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 / L-tryptophan transmembrane transporter activity / positive regulation of L-leucine import across plasma membrane / cellular response to L-arginine / alanine transport / thyroid hormone transmembrane transporter activity / apical pole of neuron / tyrosine transport / L-histidine transport / amino acid transport complex ...L-tryptophan transmembrane transport / L-tryptophan transmembrane transporter activity / positive regulation of L-leucine import across plasma membrane / cellular response to L-arginine / alanine transport / thyroid hormone transmembrane transporter activity / apical pole of neuron / tyrosine transport / L-histidine transport / amino acid transport complex / aromatic amino acid transmembrane transporter activity / L-leucine import across plasma membrane / L-alanine transmembrane transporter activity / L-alanine import across plasma membrane / Defective SLC7A7 causes lysinuric protein intolerance (LPI) / phenylalanine transport / isoleucine transport / methionine transport / valine transport / L-leucine transmembrane transporter activity / L-amino acid transmembrane transporter activity / amino acid import across plasma membrane / proline transport / thyroid hormone transport / L-leucine transport / amino acid transmembrane transport / negative regulation of vascular associated smooth muscle cell apoptotic process / neutral amino acid transport / positive regulation of cytokine production involved in immune response / neutral L-amino acid transmembrane transporter activity / amino acid transmembrane transporter activity / external side of apical plasma membrane / Amino acid transport across the plasma membrane / Tryptophan catabolism / exogenous protein binding / anchoring junction / antiporter activity / xenobiotic transport / Basigin interactions / microvillus membrane / response to muscle activity / amino acid transport / positive regulation of interleukin-4 production / response to exogenous dsRNA / positive regulation of interleukin-17 production / tryptophan transport / response to hyperoxia / transport across blood-brain barrier / cellular response to glucose starvation / positive regulation of glial cell proliferation / negative regulation of autophagy / basal plasma membrane / liver regeneration / peptide antigen binding / positive regulation of type II interferon production / calcium ion transport / melanosome / double-stranded RNA binding / virus receptor activity / cellular response to lipopolysaccharide / basolateral plasma membrane / carbohydrate metabolic process / cadherin binding / apical plasma membrane / protein heterodimerization activity / symbiont entry into host cell / lysosomal membrane / negative regulation of gene expression / intracellular membrane-bounded organelle / synapse / 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
CHOLESTEROL / 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / : / 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: 3.89 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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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)126,1196
Polymers124,1132
Non-polymers2,0064
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-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H46O
#4: Chemical ChemComp-LBN / 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / (2R)-2-[(9Z)-9-Octadecenoyloxy]-3-(palmitoyloxy)propyl 2-(trimethylammonio)ethyl phosphate


Mass: 760.076 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C42H82NO8P / Comment: phospholipid*YM
#5: Chemical ChemComp-VRW / Nanvuranlat / (2~{S})-2-azanyl-3-[4-[(5-azanyl-2-phenyl-1,3-benzoxazol-7-yl)methoxy]-3,5-bis(chloranyl)phenyl]propanoic acid


Mass: 472.321 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H19Cl2N3O4 / 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: 3.89 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 137883 / Symmetry type: POINT
RefinementResolution: 3.89→3.89 Å / Cor.coef. Fo:Fc: 0.889 / SU B: 15.379 / SU ML: 0.223 / ESU R: 0.732
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflection
Rwork0.33861 --
obs0.33861 28042 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 181.836 Å2
Refinement stepCycle: 1 / Total: 4045
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.010.0114157
ELECTRON MICROSCOPYr_bond_other_d00.0164171
ELECTRON MICROSCOPYr_angle_refined_deg1.891.6245685
ELECTRON MICROSCOPYr_angle_other_deg0.6311.5539569
ELECTRON MICROSCOPYr_dihedral_angle_1_deg6.9925504
ELECTRON MICROSCOPYr_dihedral_angle_2_deg18.6116.520
ELECTRON MICROSCOPYr_dihedral_angle_3_deg14.61610651
ELECTRON MICROSCOPYr_dihedral_angle_4_deg
ELECTRON MICROSCOPYr_chiral_restr0.0880.2685
ELECTRON MICROSCOPYr_gen_planes_refined0.0040.024617
ELECTRON MICROSCOPYr_gen_planes_other0.0010.02933
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_it30.05115.242025
ELECTRON MICROSCOPYr_mcbond_other30.05115.2412025
ELECTRON MICROSCOPYr_mcangle_it40.41427.632526
ELECTRON MICROSCOPYr_mcangle_other40.40727.642527
ELECTRON MICROSCOPYr_scbond_it39.14119.6632132
ELECTRON MICROSCOPYr_scbond_other39.13219.6612133
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other58.52734.4713160
ELECTRON MICROSCOPYr_long_range_B_refined58.331193.8216702
ELECTRON MICROSCOPYr_long_range_B_other58.329193.8216703
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 3.7→3.796 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork1.629 2096 -
obs--100 %

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