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- PDB-9pvm: cryoEM structure of drug bound human SLC33A1 transporter -

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Basic information

Entry
Database: PDB / ID: 9pvm
TitlecryoEM structure of drug bound human SLC33A1 transporter
ComponentsAcetyl-coenzyme A transporter 1
KeywordsMEMBRANE PROTEIN / solute carrier / ER membrane transporter / cryoEM / drug binding
Function / homology
Function and homology information


acetyl-CoA transmembrane transporter activity / acetyl-CoA transmembrane transport / Defective SLC33A1 causes spastic paraplegia 42 (SPG42) / Transport of vitamins, nucleosides, and related molecules / transmembrane transport / Golgi membrane / endoplasmic reticulum membrane / protein homodimerization activity / membrane / plasma membrane
Similarity search - Function
Acetyl-coenzyme A transporter 1-like / Acetyl-coenzyme A transporter 1 / AmpG-like permease/Acetyl-coenzyme A transporter 1 / MFS transporter superfamily
Similarity search - Domain/homology
: / CHOLESTEROL HEMISUCCINATE / Acetyl-coenzyme A transporter 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.27 Å
AuthorsRafiq, M. / Lander, G.C.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)AG046495 United States
CitationJournal: bioRxiv / Year: 2026
Title: Pharmacological Inhibition of SLC33A1 Promotes Endoplasmic Reticulum Hyperoxidation and Induces Adaptive IRE1/XBP1s Signaling.
Authors: Sergei Kutseikin / Maria Rafiq / Prerona Bora / Shanshan Liu / Rick A Homan / Jeffrey T Mindrebo / Matthew Holcomb / H Michael Petrassi / Huang Qiu / Anastasiya Redkina / Justyna Sosna / ...Authors: Sergei Kutseikin / Maria Rafiq / Prerona Bora / Shanshan Liu / Rick A Homan / Jeffrey T Mindrebo / Matthew Holcomb / H Michael Petrassi / Huang Qiu / Anastasiya Redkina / Justyna Sosna / Thanh-Trang Lee / Xiao Hu / Stefano Forli / Christopher G Parker / Gabriel C Lander / Kivanc Birsoy / Enrique Saez / R Luke Wiseman /
Abstract: The endoplasmic reticulum (ER) transporter solute carrier family 33 member 1 (SLC33A1) has emerged as an attractive therapeutic target in etiologically diverse diseases, ranging from lung cancer to ...The endoplasmic reticulum (ER) transporter solute carrier family 33 member 1 (SLC33A1) has emerged as an attractive therapeutic target in etiologically diverse diseases, ranging from lung cancer to neurodegenerative disorders. Yet, no pharmacologic SLC33A1 modulators have been described. Here, we show that the small molecule IXA4, a highly selective activator of the adaptive IRE1/XBP1s signaling arm of the unfolded protein response (UPR), binds to SLC33A1 and inhibits its activity. Genetic depletion of phenocopies the selective induction of IRE1/XBP1s signaling brought about by IXA4 treatment. Chemoproteomic analyses and cryo-electron microscopy show that IXA4 binds SLC33A1 within the central channel to inhibit transport of its substrate metabolite(s). Binding of IXA4 to SLC33A1 leads to the accumulation of oxidized glutathione within the ER, hyperoxidizing the ER lumen and inducing activation of adaptive IRE1/XBP1s signaling. Consistent with this function, we find that pharmacologic inhibition of SLC33A1 with IXA4 selectively reduces viability of KEAP1-deficient lung adenocarcinoma cells that have elevated levels of glutathione, mimicking the sensitivity of these cells to genetic deletion of SLC33A1. Our work demonstrates a new physiologic role of SLC33A1 in regulation of ER redox homeostasis and designates IXA4 as a pharmacologic inhibitor of SLC33A1 that can be used to evaluate the biological impact and therapeutic utility of SLC33A1 inhibition in homeostasis and in disease.
History
DepositionAug 1, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 26, 2026Provider: repository / Type: Initial release
Revision 1.0Aug 26, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Acetyl-coenzyme A transporter 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,7864
Polymers64,3761
Non-polymers1,4103
Water00
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 Acetyl-coenzyme A transporter 1 / AT-1 / Acetyl-CoA transporter 1 / Solute carrier family 33 member 1


Mass: 64376.145 Da / Num. of mol.: 1 / Mutation: no
Source method: isolated from a genetically manipulated source
Details: Wild type, full length SLC33A11 / Source: (gene. exp.) Homo sapiens (human) / Cell line: Expi293 GnTI- / Gene: SLC33A1, ACATN, AT1 / Plasmid: pCDNA3.1
Details (production host): Full-length human SLC33A1 cloned into pCDNA3.1 for expression in Expi293 GnTI- cells
Cell (production host): Expi293 / Cell line (production host): Expi293 / Production host: Homo sapiens (human) / Tissue (production host): embryonic kidney / Variant (production host): GnTI- / References: UniProt: O00400
#2: Chemical ChemComp-A1CTY / N-[1-(2-{methyl[2-(4-methylphenoxy)ethyl]amino}-2-oxoethyl)-1H-pyrazol-4-yl]-3-phenoxypropanamide


Mass: 436.504 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H28N4O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C31H50O4
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: Full length SLC33A1 with ligand bound / Type: COMPLEX
Details: Reconstituted into MSP1D1 and (POPC:DOPE:PS)lipid used
Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 64.3 kDa/nm / Experimental value: NO
Source (natural)Organism: Homo sapiens (human) / Cellular location: Endoplasmic reticulum
Source (recombinant)Organism: Homo sapiens (human) / Cell: Expi293 GnTI- / Plasmid: pcDNA3.1
Buffer solutionpH: 8 / Details: 150mM NaCl, 20mM Tris pH 8.0
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMSodium chlorideNaCl1
220 mMTris-HClC4H11NO3.HCl1
SpecimenConc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: Protin was solubilized in DDM-CHS, buffer exchanged to LMNG-CHS and reconstituted into nanodisc using MSP1D1 and lipids POPC DOPE PS
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R0./1
VitrificationInstrument: HOMEMADE PLUNGER / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 277.15 K

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 190000 X / Calibrated magnification: 189189 X / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / C2 aperture diameter: 30 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Temperature (max): 77 K / Temperature (min): 70 K
Image recordingAverage exposure time: 3.29 sec. / Electron dose: 40 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k) / Num. of grids imaged: 4 / Num. of real images: 6468
Image scansSampling size: 14 µm / Width: 4096 / Height: 4096

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.7.0particle selection
2EPU3.9.1.8206image acquisition
4cryoSPARC4.7.0CTF correction
7Coot0.9.8.95 EL(ccp4)model fitting
9cryoSPARC4.7.0initial Euler assignment
10cryoSPARC4.7.0final Euler assignment
12cryoSPARC4.7.03D reconstruction
13PHENIX1.21.1_5286model refinement
CTF correctionType: PHASE FLIPPING ONLY
Particle selectionNum. of particles selected: 3119666
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.27 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 457520 / Algorithm: FOURIER SPACE / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingB value: 180 / Protocol: RIGID BODY FIT
Atomic model buildingSource name: AlphaFold / Type: in silico model
RefinementHighest resolution: 3.27 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0043703
ELECTRON MICROSCOPYf_angle_d0.5265066
ELECTRON MICROSCOPYf_dihedral_angle_d10.274627
ELECTRON MICROSCOPYf_chiral_restr0.036593
ELECTRON MICROSCOPYf_plane_restr0.005602

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