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- EMDB-33408: Structure of human excitatory amino acid transporter 2 (EAAT2) in... -

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Basic information

Entry
Database: EMDB / ID: EMD-33408
TitleStructure of human excitatory amino acid transporter 2 (EAAT2) in complex with WAY-213613
Map dataEAAT2_WAY213.mrc
Sample
  • Complex: transporter
    • Protein or peptide: Excitatory amino acid transporter 2
  • Ligand: (2S)-2-azanyl-4-[[4-[2-bromanyl-4,5-bis(fluoranyl)phenoxy]phenyl]amino]-4-oxidanylidene-butanoic acid
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: dodecyl beta-D-glucopyranoside
KeywordsGlutamate transport / TRANSPORT PROTEIN
Function / homology
Function and homology information


neurotransmitter reuptake / membrane protein complex / Astrocytic Glutamate-Glutamine Uptake And Metabolism / cysteine transmembrane transporter activity / high-affinity L-glutamate transmembrane transporter activity / glutamate:sodium symporter activity / visual behavior / Transport of inorganic cations/anions and amino acids/oligopeptides / L-glutamate transmembrane transporter activity / L-glutamate transmembrane transport ...neurotransmitter reuptake / membrane protein complex / Astrocytic Glutamate-Glutamine Uptake And Metabolism / cysteine transmembrane transporter activity / high-affinity L-glutamate transmembrane transporter activity / glutamate:sodium symporter activity / visual behavior / Transport of inorganic cations/anions and amino acids/oligopeptides / L-glutamate transmembrane transporter activity / L-glutamate transmembrane transport / glutathione biosynthetic process / D-aspartate import across plasma membrane / L-aspartate transmembrane transport / telencephalon development / monoatomic anion transmembrane transporter activity / L-aspartate import across plasma membrane / Glutamate Neurotransmitter Release Cycle / neutral L-amino acid transmembrane transporter activity / L-glutamate import across plasma membrane / astrocyte projection / transepithelial transport / neuron projection terminus / cellular response to cocaine / neurotransmitter transport / protein homotrimerization / adult behavior / axolemma / response to amino acid / transport across blood-brain barrier / monoatomic ion transport / positive regulation of D-glucose import / response to wounding / multicellular organism growth / presynaptic membrane / cell body / vesicle / chemical synaptic transmission / membrane raft / response to xenobiotic stimulus / glutamatergic synapse / cell surface / metal ion binding / membrane / plasma membrane
Similarity search - Function
: / Sodium:dicarboxylate symporter family signature 2. / Sodium:dicarboxylate symporter / Sodium:dicarboxylate symporter, conserved site / Sodium:dicarboxylate symporter superfamily / Sodium:dicarboxylate symporter family / Sodium:dicarboxylate symporter family signature 1.
Similarity search - Domain/homology
Excitatory amino acid transporter 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsYan Z / Zhenglai Z
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Commun / Year: 2022
Title: Structural basis of ligand binding modes of human EAAT2.
Authors: Zhenglai Zhang / Huiwen Chen / Ze Geng / Zhuoya Yu / Hang Li / Yanli Dong / Hongwei Zhang / Zhuo Huang / Juquan Jiang / Yan Zhao /
Abstract: In the central nervous system (CNS), excitatory amino acid transporters (EAATs) mediate the uptake of excitatory neurotransmitter glutamate and maintain its low concentrations in the synaptic cleft ...In the central nervous system (CNS), excitatory amino acid transporters (EAATs) mediate the uptake of excitatory neurotransmitter glutamate and maintain its low concentrations in the synaptic cleft for avoiding neuronal cytotoxicity. Dysfunction of EAATs can lead to many psychiatric diseases. Here we report cryo-EM structures of human EAAT2 in an inward-facing conformation, in the presence of substrate glutamate or selective inhibitor WAY-213613. The glutamate is coordinated by extensive hydrogen bonds and further stabilized by HP2. The inhibitor WAY-213613 occupies a similar binding pocket to that of the substrate glutamate. Upon association with the WAY-213613, the HP2 undergoes a substantial conformational change, and in turn stabilizes the inhibitor binding by forming hydrophobic interactions. Electrophysiological experiments elucidate that the unique S441 plays pivotal roles in the binding of hEAAT2 with glutamate or WAY-213613, and the I464-L467-V468 cluster acts as a key structural determinant for the selective inhibition of this transporter by WAY-213613.
History
DepositionMay 9, 2022-
Header (metadata) releaseJun 22, 2022-
Map releaseJun 22, 2022-
UpdateJul 2, 2025-
Current statusJul 2, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_33408.png

Downloads & links

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Map

FileDownload / File: emd_33408.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationEAAT2_WAY213.mrc
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.04 Å/pix.
x 256 pix.
= 266.24 Å		1.04 Å/pix.
x 256 pix.
= 266.24 Å		1.04 Å/pix.
x 256 pix.
= 266.24 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.04 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.45
Minimum - Maximum-2.4803536 - 3.797376
Average (Standard dev.)0.0008985505 (±0.08982089)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 266.24 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: map half A.mrc

Fileemd_33408_half_map_1.map
Annotationmap_half_A.mrc
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: map half B.mrc

Fileemd_33408_half_map_2.map
Annotationmap_half_B.mrc
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : transporter

EntireName: transporter
Components
  • Complex: transporter
    • Protein or peptide: Excitatory amino acid transporter 2
  • Ligand: (2S)-2-azanyl-4-[[4-[2-bromanyl-4,5-bis(fluoranyl)phenoxy]phenyl]amino]-4-oxidanylidene-butanoic acid
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: dodecyl beta-D-glucopyranoside

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Supramolecule #1: transporter

SupramoleculeName: transporter / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Excitatory amino acid transporter 2

MacromoleculeName: Excitatory amino acid transporter 2 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 62.164977 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MASTEGANNM PKQVEVRMHD SHLGSEEPKH RHLGLRLCDK LGKNLLLTLT VFGVILGAVC GGLLRLASPI HPDVVMLIAF PGDILMRML KMLILPLIIS SLITGLSGLD AKASGRLGTR AMVYYMSTTI IAAVLGVILV LAIHPGNPKL KKQLGPGKKN D EVSSLDAF ...String:
MASTEGANNM PKQVEVRMHD SHLGSEEPKH RHLGLRLCDK LGKNLLLTLT VFGVILGAVC GGLLRLASPI HPDVVMLIAF PGDILMRML KMLILPLIIS SLITGLSGLD AKASGRLGTR AMVYYMSTTI IAAVLGVILV LAIHPGNPKL KKQLGPGKKN D EVSSLDAF LDLIRNLFPE NLVQACFQQI QTVTKKVLVA PPPDEEANAT SAVVSLLNET VTEVPEETKM VIKKGLEFKD GM NVLGLIG FFIAFGIAMG KMGDQAKLMV DFFNILNEIV MKLVIMIMWY SPLGIACLIC GKIIAIKDLE VVARQLGMYM VTV IIGLII HGGIFLPLIY FVVTRKNPFS FFAGIFQAWI TALGTASSAG TLPVTFRCLE ENLGIDKRVT RFVLPVGATI NMDG TALYE AVAAIFIAQM NGVVLDGGQI VTVSLTATLA SVGAASIPSA GLVTMLLILT AVGLPTEDIS LLVAVDWLLD RMRTS VNVV GDSFGAGIVY HLSKSELDTI DSQHRVHEDI EMTKTQSIYD DMKNHRESNS NQCVYAAHNS VIVDECKVTL AANGKS ADC SVEEEPWKRE K

UniProtKB: Excitatory amino acid transporter 2

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Macromolecule #2: (2S)-2-azanyl-4-[[4-[2-bromanyl-4,5-bis(fluoranyl)phenoxy]phenyl]...

MacromoleculeName: (2S)-2-azanyl-4-[[4-[2-bromanyl-4,5-bis(fluoranyl)phenoxy]phenyl]amino]-4-oxidanylidene-butanoic acid
type: ligand / ID: 2 / Number of copies: 3 / Formula: GJ0
Molecular weightTheoretical: 415.186 Da
Chemical component information

ChemComp-GJ0:
(2S)-2-azanyl-4-[[4-[2-bromanyl-4,5-bis(fluoranyl)phenoxy]phenyl]amino]-4-oxidanylidene-butanoic acid / inhibitor*YM

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Macromolecule #3: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 3 / Number of copies: 3 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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Macromolecule #4: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE

MacromoleculeName: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 4 / Number of copies: 30 / Formula: PC1
Molecular weightTheoretical: 790.145 Da
Chemical component information

ChemComp-PC1:
1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / phospholipid*YM

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Macromolecule #5: dodecyl beta-D-glucopyranoside

MacromoleculeName: dodecyl beta-D-glucopyranoside / type: ligand / ID: 5 / Number of copies: 3 / Formula: XKJ
Molecular weightTheoretical: 348.475 Da
Chemical component information

ChemComp-XKJ:
dodecyl beta-D-glucopyranoside / detergent*YM

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 420
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD

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