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- PDB-9p4x: Human EAAT3 with compound 3e and cholesterol bound at inward faci... -

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Basic information

Entry
Database: PDB / ID: 9p4x
TitleHuman EAAT3 with compound 3e and cholesterol bound at inward facing state
ComponentsExcitatory amino acid transporter 3
KeywordsTRANSPORT PROTEIN / hEAAAT3 / allosteric inhibitor
Function / homology
Function and homology information


D-aspartate transmembrane transport / regulation of protein targeting to membrane / D-aspartate transmembrane transporter activity / Defective SLC1A1 is implicated in schizophrenia 18 (SCZD18) and dicarboxylic aminoaciduria (DCBXA) / distal dendrite / cysteine transport / cysteine transmembrane transporter activity / neurotransmitter receptor transport to plasma membrane / high-affinity L-glutamate transmembrane transporter activity / glutamate:sodium symporter activity ...D-aspartate transmembrane transport / regulation of protein targeting to membrane / D-aspartate transmembrane transporter activity / Defective SLC1A1 is implicated in schizophrenia 18 (SCZD18) and dicarboxylic aminoaciduria (DCBXA) / distal dendrite / cysteine transport / cysteine transmembrane transporter activity / neurotransmitter receptor transport to plasma membrane / high-affinity L-glutamate transmembrane transporter activity / glutamate:sodium symporter activity / response to decreased oxygen levels / L-glutamate import / cellular response to mercury ion / Transport of inorganic cations/anions and amino acids/oligopeptides / retina layer formation / L-glutamate transmembrane transporter activity / L-glutamate transmembrane transport / glutathione biosynthetic process / D-aspartate import across plasma membrane / L-aspartate transmembrane transport / cellular response to ammonium ion / righting reflex / zinc ion transmembrane transport / cellular response to bisphenol A / L-aspartate transmembrane transporter activity / grooming behavior / intracellular glutamate homeostasis / L-aspartate import across plasma membrane / Glutamate Neurotransmitter Release Cycle / monoatomic anion channel activity / L-glutamate import across plasma membrane / proximal dendrite / transepithelial transport / apical dendrite / intracellular zinc ion homeostasis / conditioned place preference / cellular response to cocaine / blood vessel morphogenesis / chloride transmembrane transporter activity / motor neuron apoptotic process / response to morphine / G protein-coupled dopamine receptor signaling pathway / glutamate receptor signaling pathway / response to anesthetic / neurotransmitter transport / maintenance of blood-brain barrier / superoxide metabolic process / heart contraction / perisynaptic space / dopamine metabolic process / motor behavior / adult behavior / asymmetric synapse / glial cell projection / behavioral fear response / postsynaptic modulation of chemical synaptic transmission / synaptic cleft / response to axon injury / transport across blood-brain barrier / positive regulation of heart rate / monoatomic ion transport / axon terminus / neurogenesis / response to amphetamine / chloride transmembrane transport / dendritic shaft / cell periphery / locomotory behavior / synapse organization / brain development / cytokine-mediated signaling pathway / Schaffer collateral - CA1 synapse / long-term synaptic potentiation / memory / recycling endosome membrane / late endosome membrane / presynapse / cellular response to oxidative stress / early endosome membrane / chemical synaptic transmission / dendritic spine / perikaryon / negative regulation of neuron apoptotic process / gene expression / apical plasma membrane / membrane raft / response to xenobiotic stimulus / axon / neuronal cell body / dendrite / cell surface / extracellular exosome / metal ion binding / identical protein 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
: / CHOLESTEROL / Excitatory amino acid transporter 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.76 Å
AuthorsQiu, B. / Boudker, O.
Funding support United States, 1items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI)NA United States
CitationJournal: bioRxiv / Year: 2025
Title: Mechanism and Structure-Guided Optimization of SLC1A1/EAAT3-Selective Inhibitors in Kidney Cancer.
Authors: Pooneh Koochaki / Biao Qiu / Jesse A Coker / Alexander Earsley / Nancy S Wang / Todd Romigh / Christopher M Goins / Shaun R Stauffer / Olga Boudker / Abhishek A Chakraborty
Abstract: Renal Cell Carcinomas (RCCs) depend metabolically on the trimeric sodium-coupled aspartate and glutamate transporter, SLC1A1/EAAT3; however, pharmacologically targeting SLC1A1 is challenging. We ...Renal Cell Carcinomas (RCCs) depend metabolically on the trimeric sodium-coupled aspartate and glutamate transporter, SLC1A1/EAAT3; however, pharmacologically targeting SLC1A1 is challenging. We determined a cryo-EM structure of human SLC1A1 bound to compound , a recently described SLC1A1-selective bicyclic imidazo[1,2- ]pyridine-3-amine (BIA) inhibitor. binds a membrane-embedded, allosteric pocket accessible only in the state, when SLC1A1 is unbound to substrate and sodium. Wedged between the trimerization domain and the substrate-binding transport domain, together with a cholesterol moiety from the lipid bilayer, likely prevents sodium and substrate binding, and blocks SLC1A1's elevator-like movements that are essential for transport. Mutations in this pocket abolish binding and counteract 's cytotoxicity in RCC cells, confirming on-target activity and explaining SLC1A1 selectivity. A structure-guided medicinal chemistry effort yielded two new, SLC1A1- selective BIA derivatives, PBJ1 and PBJ2, with enhanced cytotoxicity resulting from the inhibition of SLC1A1-dependent aspartate, glutamate, and cysteine metabolic pathways.
History
DepositionJun 17, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 30, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Excitatory amino acid transporter 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,4174
Polymers57,2751
Non-polymers1,1423
Water724
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Excitatory amino acid transporter 3 / Excitatory amino-acid carrier 1 / Neuronal and epithelial glutamate transporter / Sodium-dependent ...Excitatory amino-acid carrier 1 / Neuronal and epithelial glutamate transporter / Sodium-dependent glutamate/aspartate transporter 3 / Solute carrier family 1 member 1


Mass: 57275.168 Da / Num. of mol.: 1 / Mutation: N178T, N195T
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC1A1, EAAC1, EAAT3, HEAAC1 / Production host: Homo sapiens (human) / References: UniProt: P43005
#2: Chemical ChemComp-A1CG9 / (4R)-8-bromo-2-(furan-2-yl)-N-(2-methylphenyl)imidazo[1,2-a]pyridin-3-amine


Mass: 368.227 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H14BrN3O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H46O / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: human excitatory amino acid transporter 3 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.56 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenConc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 298 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 58 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameCategory
2Leginonimage acquisition
7UCSF ChimeraXmodel fitting
9cryoSPARCinitial Euler assignment
10cryoSPARCfinal Euler assignment
11cryoSPARCclassification
12cryoSPARC3D reconstruction
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 6652777
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.76 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 165757 / Symmetry type: POINT
Atomic model buildingB value: 46.66 / Protocol: OTHER
Atomic model buildingPDB-ID: 6X3F

6x3f


Accession code: 6X3F / Source name: PDB / Type: experimental model

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