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- PDB-7xr6: Structure of human excitatory amino acid transporter 2 (EAAT2) in... -

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Basic information

Entry
Database: PDB / ID: 7xr6
TitleStructure of human excitatory amino acid transporter 2 (EAAT2) in complex with WAY-213613
ComponentsExcitatory amino acid transporter 2
KeywordsTRANSPORT PROTEIN / Glutamate transport
Function / homology
Function and homology information


neurotransmitter reuptake / Astrocytic Glutamate-Glutamine Uptake And Metabolism / membrane protein complex / 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 transport / L-glutamate transmembrane transporter activity ...neurotransmitter reuptake / Astrocytic Glutamate-Glutamine Uptake And Metabolism / membrane protein complex / 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 transport / L-glutamate transmembrane transporter activity / L-aspartate transmembrane transport / glutathione biosynthetic process / D-aspartate import across plasma membrane / telencephalon development / L-aspartate import across plasma membrane / Glutamate Neurotransmitter Release Cycle / monoatomic anion transmembrane transporter activity / neutral L-amino acid transmembrane transporter activity / L-glutamate import across plasma membrane / transepithelial transport / astrocyte projection / neuron projection terminus / cellular response to cocaine / neurotransmitter transport / adult behavior / protein homotrimerization / transport across blood-brain barrier / axolemma / response to amino acid / monoatomic ion transport / positive regulation of D-glucose import / multicellular organism growth / response to wounding / presynaptic membrane / cell body / chemical synaptic transmission / vesicle / response to xenobiotic stimulus / membrane raft / glutamatergic synapse / cell surface / membrane / metal ion binding / 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
Chem-GJ0 / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / dodecyl beta-D-glucopyranoside / CHOLESTEROL HEMISUCCINATE / Excitatory amino acid transporter 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsZhao, Y. / Zhang, Z.
Funding support China, 1items
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, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 22, 2022Provider: repository / Type: Initial release
Revision 1.1Jul 3, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond / em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Excitatory amino acid transporter 2
B: Excitatory amino acid transporter 2
C: Excitatory amino acid transporter 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)213,95042
Polymers186,4953
Non-polymers27,45639
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Excitatory amino acid transporter 2 / Glutamate/aspartate transporter II / Sodium-dependent glutamate/aspartate transporter 2 / Solute ...Glutamate/aspartate transporter II / Sodium-dependent glutamate/aspartate transporter 2 / Solute carrier family 1 member 2


Mass: 62164.977 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC1A2, EAAT2, GLT1 / Production host: Homo sapiens (human) / References: UniProt: P43004
#2: Chemical ChemComp-GJ0 / (2S)-2-azanyl-4-[[4-[2-bromanyl-4,5-bis(fluoranyl)phenoxy]phenyl]amino]-4-oxidanylidene-butanoic acid / WAY-213613


Mass: 415.186 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C16H13BrF2N2O4 / Feature type: SUBJECT OF INVESTIGATION / Comment: inhibitor*YM
#3: Chemical ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C31H50O4
#4: Chemical...
ChemComp-PC1 / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / 3-SN-PHOSPHATIDYLCHOLINE


Mass: 790.145 Da / Num. of mol.: 30 / Source method: obtained synthetically / Formula: C44H88NO8P / Comment: phospholipid*YM
#5: Sugar ChemComp-XKJ / dodecyl beta-D-glucopyranoside


Type: D-saccharide / Mass: 348.475 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C18H36O6 / Comment: detergent*YM
Has ligand of interestY

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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: transporter / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 420 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00410328
ELECTRON MICROSCOPYf_angle_d0.58713852
ELECTRON MICROSCOPYf_dihedral_angle_d19.6371719
ELECTRON MICROSCOPYf_chiral_restr0.0411709
ELECTRON MICROSCOPYf_plane_restr0.0041617

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