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- EMDB-37132: Structure of LAT1-CD98hc-Fab170 in complex with JPH203, consensus map -

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Basic information

Entry
Database: EMDB / ID: EMD-37132
TitleStructure of LAT1-CD98hc-Fab170 in complex with JPH203, consensus map
Map data
Sample
  • Complex: LAT1-CD98hc-Fab170
    • Complex: LAT1-CD98hc
      • Protein or peptide: 4F2 cell-surface antigen heavy chain
      • Protein or peptide: Large neutral amino acids transporter small subunit 1
    • Complex: Fab170
      • Protein or peptide: Fab170 heavy chain
      • Protein or peptide: Fab170 light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: Nanvuranlat
KeywordsTransporter / Amino acid / Complex / Cancer / TRANSPORT PROTEIN
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 / antiporter activity / anchoring junction / Basigin interactions / xenobiotic transport / 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 / 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
Amino acid transporter heavy chain SLC3A2 / Large neutral amino acids transporter small subunit 1
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.83 Å
AuthorsLee Y
Funding support Germany, 1 items
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, 2023-
Header (metadata) releaseFeb 12, 2025-
Map releaseFeb 12, 2025-
UpdateFeb 26, 2025-
Current statusFeb 26, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_37132.png

Downloads & links

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Map

FileDownload / File: emd_37132.map.gz / Format: CCP4 / Size: 9.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.53 Å/pix.
x 136 pix.
= 208.692 Å		1.53 Å/pix.
x 136 pix.
= 208.692 Å		1.53 Å/pix.
x 136 pix.
= 208.692 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.5345 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.04
Minimum - Maximum-0.20837636 - 0.31053188
Average (Standard dev.)0.0008904442 (±0.008065117)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions136136136
Spacing136136136
CellA=B=C: 208.692 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_37132_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_37132_half_map_1.map
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_37132_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : LAT1-CD98hc-Fab170

EntireName: LAT1-CD98hc-Fab170
Components
  • Complex: LAT1-CD98hc-Fab170
    • Complex: LAT1-CD98hc
      • Protein or peptide: 4F2 cell-surface antigen heavy chain
      • Protein or peptide: Large neutral amino acids transporter small subunit 1
    • Complex: Fab170
      • Protein or peptide: Fab170 heavy chain
      • Protein or peptide: Fab170 light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: Nanvuranlat

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Supramolecule #1: LAT1-CD98hc-Fab170

SupramoleculeName: LAT1-CD98hc-Fab170 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2, #4, #3
Molecular weightTheoretical: 173 KDa

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Supramolecule #2: LAT1-CD98hc

SupramoleculeName: LAT1-CD98hc / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: Fab170

SupramoleculeName: Fab170 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #4, #3
Source (natural)Organism: Mus musculus (house mouse)

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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: 68.069625 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GSELQPPEAS IAVVSIPRQL PGSHSEAGVQ GLSAGDDSEL GSHCVAQTGL ELLASGDPLP SASQNAEMIE TGSDCVTQAG LQLLASSDP PALASKNAEV TGTMSQDTEV DMKEVELNEL EPEKQPMNAA SGAAMSLAGA EKNGLVKIKV AEDEAEAAAA A KFTGLSKE ...String:
GSELQPPEAS IAVVSIPRQL PGSHSEAGVQ GLSAGDDSEL GSHCVAQTGL ELLASGDPLP SASQNAEMIE TGSDCVTQAG LQLLASSDP PALASKNAEV TGTMSQDTEV DMKEVELNEL EPEKQPMNAA SGAAMSLAGA EKNGLVKIKV AEDEAEAAAA A KFTGLSKE ELLKVAGSPG WVRTRWALLL LFWLGWLGML AGAVVIIVRA PRCRELPAQK WWHTGALYRI GDLQAFQGHG AG NLAGLKG RLDYLSSLKV KGLVLGPIHK NQKDDVAQTD LLQIDPNFGS KEDFDSLLQS AKKKSIRVIL DLTPNYRGEN SWF STQVDT VATKVKDALE FWLQAGVDGF QVRDIENLKD ASSFLAEWQN ITKGFSEDRL LIAGTNSSDL QQILSLLESN KDLL LTSSY LSDSGSTGEH TKSLVTQYLN ATGNRWCSWS LSQARLLTSF LPAQLLRLYQ LMLFTLPGTP VFSYGDEIGL DAAAL PGQP MEAPVMLWDE SSFPDIPGAV SANMTVKGQS EDPGSLLSLF RRLSDQRSKE RSLLHGDFHA FSAGPGLFSY IRHWDQ NER FLVVLNFGDV GLSAGLQASD LPASASLPAK ADLLLSTQPG REEGSPLELE RLKLEPHEGL LLRFPYAA

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: 56.043746 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAGAGPKRRA LAAPAAEEKE EAREKMLAAK SADGSAPAGE GEGVTLQRNI TLLNGVAIIV GTIIGSGIFV TPTGVLKEAG SPGLALVVW AACGVFSIVG ALCYAELGTT ISKSGGDYAY MLEVYGSLPA FLKLWIELLI IRPSSQYIVA LVFATYLLKP L FPTCPVPE ...String:
MAGAGPKRRA LAAPAAEEKE EAREKMLAAK SADGSAPAGE GEGVTLQRNI TLLNGVAIIV GTIIGSGIFV TPTGVLKEAG SPGLALVVW AACGVFSIVG ALCYAELGTT ISKSGGDYAY MLEVYGSLPA FLKLWIELLI IRPSSQYIVA LVFATYLLKP L FPTCPVPE EAAKLVACLC VLLLTAVNCY SVKAATRVQD AFAAAKLLAL ALIILLGFVQ IGKGDVSNLD PNFSFEGTKL DV GNIVLAL YSGLFAYGGW NYLNFVTEEM INPYRNLPLA IIISLPIVTL VYVLTNLAYF TTLSTEQMLS SEAVAVDFGN YHL GVMSWI IPVFVGLSCF GSVNGSLFTS SRLFFVGSRE GHLPSILSMI HPQLLTPVPS LVFTCVMTLL YAFSKDIFSV INFF SFFNW LCVALAIIGM IWLRHRKPEL ERPIKVNLAL PVFFILACLF LIAVSFWKTP VECGIGFTII LSGLPVYFFG VWWKN KPKW LLQGIFSTTV LCQKLMQVVP QETDYKDDDD K

UniProtKB: Large neutral amino acids transporter small subunit 1

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Macromolecule #3: Fab170 light chain

MacromoleculeName: Fab170 light chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 24.355986 KDa
SequenceString: DIVLTQSPSS LAMSVGQKVT MNCKSSQSLL NNNNQKNYLA WYQQKPGQSP KLLVYFTSTR ESGVPDRFIG SGSGTDFTLT ISSVQAEDL ALYYCQQHYT IPPTFGGGTK LEIKRADAAP TVSIFPPSSE QLTSGGASVV CFLNNFYPKD INVKWKIDGS E RQNGVLNS ...String:
DIVLTQSPSS LAMSVGQKVT MNCKSSQSLL NNNNQKNYLA WYQQKPGQSP KLLVYFTSTR ESGVPDRFIG SGSGTDFTLT ISSVQAEDL ALYYCQQHYT IPPTFGGGTK LEIKRADAAP TVSIFPPSSE QLTSGGASVV CFLNNFYPKD INVKWKIDGS E RQNGVLNS WTDQDSKDST YSMSSTLTLT KDEYERHNSY TCEATHKTST SPIVKSFNRN EC

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Macromolecule #4: Fab170 heavy chain

MacromoleculeName: Fab170 heavy chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 24.981906 KDa
SequenceString: EVQLQQSGAE LVKPGASVNL SCKASGYTFT NYWMHWVRLR PGQGLEWIGE IDPSDSYSYY SQNFKGKATL TVDQSSNTAY LQLTSLTSE DSAVYYCARG RQTYYPWFPY WGQGTLVTVS AAKTTPPSDY PLAPGSAAQT NSMVTLGCLV KGYFPEPVTV T WNSGSLSS ...String:
EVQLQQSGAE LVKPGASVNL SCKASGYTFT NYWMHWVRLR PGQGLEWIGE IDPSDSYSYY SQNFKGKATL TVDQSSNTAY LQLTSLTSE DSAVYYCARG RQTYYPWFPY WGQGTLVTVS AAKTTPPSDY PLAPGSAAQT NSMVTLGCLV KGYFPEPVTV T WNSGSLSS GVHTFPAVLQ SDLYTLSSSV TVPSSTWPSE TVTCNVAHPA SSTKVDKKIV PRDCGCKPCI CT

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Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / Number of copies: 4 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #6: Nanvuranlat

MacromoleculeName: Nanvuranlat / type: ligand / ID: 6 / Number of copies: 1 / Formula: VRW
Molecular weightTheoretical: 472.321 Da

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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: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 51.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.83 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 137883
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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