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- EMDB-37134: Structure of LAT1-CD98hc in complex with JPH203, focused on TMD -

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Basic information

Entry
Database: EMDB / ID: EMD-37134
TitleStructure of LAT1-CD98hc in complex with JPH203, focused on TMD
Map data
Sample
  • Complex: LAT1-CD98hc-Fab170
    • Protein or peptide: 4F2 cell-surface antigen heavy chain
    • Protein or peptide: Large neutral amino acids transporter small subunit 1
  • Ligand: CHOLESTEROL
  • Ligand: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine
  • 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 / 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 / positive regulation of cytokine production involved in immune response / amino acid import across plasma membrane / 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 / anchoring junction / antiporter activity / 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
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: 3.89 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_37134.png

Downloads & links

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Map

FileDownload / File: emd_37134.map.gz / Format: CCP4 / Size: 3.6 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 98 pix.
= 150.381 Å		1.53 Å/pix.
x 98 pix.
= 150.381 Å		1.53 Å/pix.
x 98 pix.
= 150.381 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.5345 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.06
Minimum - Maximum-0.17491375 - 0.2993084
Average (Standard dev.)0.0016149128 (±0.011581098)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions989898
Spacing989898
CellA=B=C: 150.381 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_37134_msk_1.map
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AxesZYX

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Slices (1/2)
Density Histograms

Histogram

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Half map: #2

Fileemd_37134_half_map_1.map
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Half map: #1

Fileemd_37134_half_map_2.map
Projections & Slices
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Sample components

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Entire : LAT1-CD98hc-Fab170

EntireName: LAT1-CD98hc-Fab170
Components
  • Complex: LAT1-CD98hc-Fab170
    • Protein or peptide: 4F2 cell-surface antigen heavy chain
    • Protein or peptide: Large neutral amino acids transporter small subunit 1
  • Ligand: CHOLESTEROL
  • Ligand: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine
  • 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
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 173 KDa

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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: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 3 / Number of copies: 2 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #4: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine

MacromoleculeName: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / type: ligand / ID: 4 / Number of copies: 1 / Formula: LBN
Molecular weightTheoretical: 760.076 Da
Chemical component information

ChemComp-LBN:
1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / phospholipid*YM

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Macromolecule #5: Nanvuranlat

MacromoleculeName: Nanvuranlat / type: ligand / ID: 5 / 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: 3.89 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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