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- EMDB-75048: Human Excitatory Amino Acid Transporter 3 in 300 mM potassium and... -

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Basic information

Entry
Database: EMDB / ID: EMD-75048
TitleHuman Excitatory Amino Acid Transporter 3 in 300 mM potassium and 0.1 mM Cmpd 3e in the intermediate outward-facing (iOFS) state
Map dataThis is final map
Sample
  • Complex: human excitatory amino acid transporter 3
    • Protein or peptide: human excitatory amino acid transporter 3
KeywordshEAAT3 / TRANSPORT PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.11 Å
AuthorsEarsley A / Qiu B / Boudker O
Funding support United States, 1 items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: EMBO J / Year: 2026
Title: Structure-guided optimization of SLC1A1/EAAT3-selective inhibitors targeting renal cancer metabolism.
Authors: Pooneh Koochaki / Biao Qiu / Jesse A Coker / Alexander Earsley / Nancy S Wang / Todd Romigh / Christopher M Goins / Carleigh Salem / Dehui Mi / Emily Days / Joshua A Bauer / Shaun R Stauffer ...Authors: Pooneh Koochaki / Biao Qiu / Jesse A Coker / Alexander Earsley / Nancy S Wang / Todd Romigh / Christopher M Goins / Carleigh Salem / Dehui Mi / Emily Days / Joshua A Bauer / Shaun R Stauffer / Olga Boudker / Abhishek A Chakraborty /
Abstract: Renal cell carcinomas (RCCs) depend on the trimeric sodium-coupled aspartate and glutamate transporter, SLC1A1/EAAT3; however, pharmacologically targeting SLC1A1 is challenging. Here we determined a ...Renal cell carcinomas (RCCs) depend on the trimeric sodium-coupled aspartate and glutamate transporter, SLC1A1/EAAT3; however, pharmacologically targeting SLC1A1 is challenging. Here we determined a cryo-EM structure of human SLC1A1 bound to compound 3e, a recently described SLC1A1-selective bicyclic imidazo[1,2 α]pyridine-3-amine (BIA) inhibitor with an unclear mechanism of action. 3e binds a membrane-embedded allosteric pocket accessible only in the apo state, when SLC1A1 is unbound to substrate and sodium, and likely prevents sodium and substrate binding. Moreover, by forming a wedge between the trimerization domain and the substrate-binding transport domain, alongside a cholesterol moiety from the lipid bilayer, 3e blocks SLC1A1's elevator-like movements that support the transport cycle. Mutations in this binding pocket abolish the 3e interaction and counteract 3e's cytotoxicity in RCC cells, confirming on-target activity and explaining SLC1A1 selectivity. The subsequent design of two new SLC1A1-selective BIA derivatives, PBJ1 and PBJ2, was directed by the SLC1A1-3e structures; both inhibited SLC1A1-dependent aspartate, glutamate, and cysteine metabolism and showed enhanced cytotoxicity.
History
DepositionJan 9, 2026-
Header (metadata) releaseMay 6, 2026-
Map releaseMay 6, 2026-
UpdateMay 6, 2026-
Current statusMay 6, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_75048.png

Downloads & links

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Map

FileDownload / File: emd_75048.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationThis is final map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.86 Å/pix.
x 300 pix.
= 256.8 Å		0.86 Å/pix.
x 300 pix.
= 256.8 Å		0.86 Å/pix.
x 300 pix.
= 256.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.856 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.117
Minimum - Maximum-1.0924696 - 1.306395
Average (Standard dev.)0.0007155238 (±0.022494242)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 256.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: This is half map A

Fileemd_75048_half_map_1.map
AnnotationThis is half map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: This is half map B

Fileemd_75048_half_map_2.map
AnnotationThis is half map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : human excitatory amino acid transporter 3

EntireName: human excitatory amino acid transporter 3
Components
  • Complex: human excitatory amino acid transporter 3
    • Protein or peptide: human excitatory amino acid transporter 3

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Supramolecule #1: human excitatory amino acid transporter 3

SupramoleculeName: human excitatory amino acid transporter 3 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: human excitatory amino acid transporter 3

MacromoleculeName: human excitatory amino acid transporter 3 / type: protein_or_peptide / ID: 1
Details: The first and second residues, "GP," are from the rescission protease cleavage site. This protein contains mutation N178T, N195T, C9A, C100A, C158A, N178T, N195T, C219A, C256W, K269C, and W441C.
Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GPMGKPARKG AEWKRFLKNN WVLLSTVAAV VLGITTGVLV REHSNLSTLE KFYFAFPGEI LMRMLKLIIL PL IISSMIT GVAALDSNVS GKIGLRAVVY YFATTLIAVI LGIVLVVSIK PGVTQKVGEI ARTGSTPEVS TVD AMLDLI RNMFPENLVQ AAFQQYKTKR ...String:
GPMGKPARKG AEWKRFLKNN WVLLSTVAAV VLGITTGVLV REHSNLSTLE KFYFAFPGEI LMRMLKLIIL PL IISSMIT GVAALDSNVS GKIGLRAVVY YFATTLIAVI LGIVLVVSIK PGVTQKVGEI ARTGSTPEVS TVD AMLDLI RNMFPENLVQ AAFQQYKTKR EEVKPPSDPE MTMTEESFTA VMTTAISKTK TKEYKIVGMY SDGI NVLGL IVFALVFGLV IGKMGEKGQI LVDFFNALSD ATMKIVQIIM WYMPLGILFL IAGCIIEVED WEIFR KLGL YMATVLTGLA IHSIVILPLI YFIVVRKNPF RFAMGMAQAL LTALMISSSS ATLPVTFRCA EENNQV DKR ITRFVLPVGA TINMDGTALY EAVAAVFIAQ LNDLDLGIGQ IITISITATS ASIGAAGVPQ AGLVTMV IV LSAVGLPAED VTLIIAVDCL LDRFRTMVNV LGDAFGTGIV EKLSKKELEQ MDVSSEVNIV NPFALEST I LDNEDSDTKK SYVNGGFAVD KSDTISFTQT SQF

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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

Concentration4 mg/mL
BufferpH: 7.4
Details: 20 mM Hepes-Tris pH 7.4, 300 mM KCl and 0.01% GDN, 0.1 mM Cmpd3e
GridModel: Quantifoil / Material: GOLD / Mesh: 300
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 53.9 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: ab-initio
Final reconstructionNumber classes used: 8 / Resolution.type: BY AUTHOR / Resolution: 3.11 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 791674
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final 3D classificationNumber classes: 10 / Avg.num./class: 980000 / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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