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- PDB-8kdp: Structure of apo outward-open LAT1-CD98h in nanodisc, focused on TMD -

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Basic information

Entry
Database: PDB / ID: 8kdp
TitleStructure of apo outward-open LAT1-CD98h in nanodisc, 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 / alanine transport / apical pole of neuron / tyrosine transport / L-histidine transport / amino acid transport complex / L-leucine import across plasma membrane ...L-tryptophan transmembrane transport / positive regulation of L-leucine import across plasma membrane / L-tryptophan transmembrane transporter activity / cellular response to L-arginine / alanine transport / apical pole of neuron / tyrosine transport / L-histidine transport / amino acid transport complex / L-leucine import across plasma membrane / L-alanine transmembrane transporter activity / thyroid hormone 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 / amino acid transmembrane transport / L-leucine transmembrane transporter activity / isoleucine transport / valine transport / L-amino acid transmembrane transporter activity / amino acid import across plasma membrane / proline transport / 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 / neutral L-amino acid transmembrane transporter activity / external side of apical plasma membrane / amino acid transmembrane transporter activity / 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-17 production / positive regulation of interleukin-4 production / response to exogenous dsRNA / 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 / liver regeneration / basal plasma membrane / 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
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
Revision 1.0Feb 12, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 12, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 12, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Feb 12, 2025Data content type: Mask / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Feb 12, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Feb 26, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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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
Data content type: EM metadata / EM metadata ...EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata
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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


Theoretical massNumber of molelcules
Total (without water)124,1132
Polymers124,1132
Non-polymers00
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
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: all / 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: 60876 / Symmetry type: POINT
RefinementResolution: 4.12→4.12 Å / Cor.coef. Fo:Fc: 0.915 / SU B: 20.617 / SU ML: 0.287 / ESU R: 1.081
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflection
Rwork0.32791 --
obs0.32791 21438 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 215.71 Å2
Refinement stepCycle: 1 / Total: 3918
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0090.0114022
ELECTRON MICROSCOPYr_bond_other_d00.0164015
ELECTRON MICROSCOPYr_angle_refined_deg1.8591.6245492
ELECTRON MICROSCOPYr_angle_other_deg0.6281.5549200
ELECTRON MICROSCOPYr_dihedral_angle_1_deg7.815503
ELECTRON MICROSCOPYr_dihedral_angle_2_deg6.72514
ELECTRON MICROSCOPYr_dihedral_angle_3_deg15.15110651
ELECTRON MICROSCOPYr_dihedral_angle_4_deg
ELECTRON MICROSCOPYr_chiral_restr0.0850.2664
ELECTRON MICROSCOPYr_gen_planes_refined0.0040.024553
ELECTRON MICROSCOPYr_gen_planes_other0.0010.02919
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_it38.1818.1532021
ELECTRON MICROSCOPYr_mcbond_other38.14318.1552021
ELECTRON MICROSCOPYr_mcangle_it51.30932.752521
ELECTRON MICROSCOPYr_mcangle_other51.29932.7592522
ELECTRON MICROSCOPYr_scbond_it47.36823.5012001
ELECTRON MICROSCOPYr_scbond_other47.35623.5092002
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other71.60841.0362972
ELECTRON MICROSCOPYr_long_range_B_refined72.05922816294
ELECTRON MICROSCOPYr_long_range_B_other72.058228.0116295
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 4.001→4.104 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.954 1560 -
obs--100 %

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