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- EMDB-71893: cryoEM structure of drug bound human SLC33A1 transporter -

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Basic information

Entry
Database: EMDB / ID: EMD-71893
TitlecryoEM structure of drug bound human SLC33A1 transporter
Map data
Sample
  • Complex: Full length SLC33A1 with ligand bound
    • Protein or peptide: Acetyl-coenzyme A transporter 1
  • Ligand: N-[1-(2-{methyl[2-(4-methylphenoxy)ethyl]amino}-2-oxoethyl)-1H-pyrazol-4-yl]-3-phenoxypropanamide
  • Ligand: CHOLESTEROL HEMISUCCINATE
Keywordssolute carrier / ER membrane transporter / cryoEM / drug binding / MEMBRANE PROTEIN
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
Acetyl-coenzyme A transporter 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.27 Å
AuthorsRafiq M / Lander GC
Funding support United States, 1 items
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, 2025-
Header (metadata) releaseAug 26, 2026-
Map releaseAug 26, 2026-
UpdateAug 26, 2026-
Current statusAug 26, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_71893.png

Downloads & links

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Map

FileDownload / File: emd_71893.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 256 pix.
= 186.112 Å		0.73 Å/pix.
x 256 pix.
= 186.112 Å		0.73 Å/pix.
x 256 pix.
= 186.112 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.727 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.076
Minimum - Maximum-1.7593708 - 2.0535305
Average (Standard dev.)0.00020950875 (±0.048164934)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 186.112 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_71893_msk_1.map
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Additional map: #1

Fileemd_71893_additional_1.map
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Half map: #2

Fileemd_71893_half_map_1.map
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Half map: #1

Fileemd_71893_half_map_2.map
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Sample components

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Entire : Full length SLC33A1 with ligand bound

EntireName: Full length SLC33A1 with ligand bound
Components
  • Complex: Full length SLC33A1 with ligand bound
    • Protein or peptide: Acetyl-coenzyme A transporter 1
  • Ligand: N-[1-(2-{methyl[2-(4-methylphenoxy)ethyl]amino}-2-oxoethyl)-1H-pyrazol-4-yl]-3-phenoxypropanamide
  • Ligand: CHOLESTEROL HEMISUCCINATE

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Supramolecule #1: Full length SLC33A1 with ligand bound

SupramoleculeName: Full length SLC33A1 with ligand bound / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Details: Reconstituted into MSP1D1 and (POPC:DOPE:PS)lipid used
Source (natural)Organism: Homo sapiens (human) / Location in cell: Endoplasmic reticulum
Molecular weightTheoretical: 64.3 kDa/nm

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Macromolecule #1: Acetyl-coenzyme A transporter 1

MacromoleculeName: Acetyl-coenzyme A transporter 1 / type: protein_or_peptide / ID: 1 / Details: Wild type, full length SLC33A11 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 64.376145 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MHHHHHHDYK DDDDKGSSGL EVLFQGPGSS GMSPTISHKD SSRQRRPGNF SHSLDMKSGP LPPGGWDDSH LDSAGREGDR EALLGDTGT GDFLKAPQSF RAELSSILLL LFLYVLQGIP LGLAGSIPLI LQSKNVSYTD QAFFSFVFWP FSLKLLWAPL V DAVYVKNF ...String:
MHHHHHHDYK DDDDKGSSGL EVLFQGPGSS GMSPTISHKD SSRQRRPGNF SHSLDMKSGP LPPGGWDDSH LDSAGREGDR EALLGDTGT GDFLKAPQSF RAELSSILLL LFLYVLQGIP LGLAGSIPLI LQSKNVSYTD QAFFSFVFWP FSLKLLWAPL V DAVYVKNF GRRKSWLVPT QYILGLFMIY LSTQVDRLLG NTDDRTPDVI ALTVAFFLFE FLAATQDIAV DGWALTMLSR EN VGYASTC NSVGQTAGYF LGNVLFLALE SADFCNKYLR FQPQPRGIVT LSDFLFFWGT VFLITTTLVA LLKKENEVSV VKE ETQGIT DTYKLLFAII KMPAVLTFCL LILTAKIGFS AADAVTGLKL VEEGVPKEHL ALLAVPMVPL QIILPLIISK YTAG PQPLN TFYKAMPYRL LLGLEYALLV WWTPKVEHQG GFPIYYYIVV LLSYALHQVT VYSMYVSIMA FNAKVSDPLI GGTYM TLLN TVSNLGGNWP STVALWLVDP LTVKECVGAS NQNCRTPDAV ELCKKLGGSC VTALDGYYVE SIICVFIGFG WWFFLG PKF KKLQDEGSSS WKCKRNN

UniProtKB: Acetyl-coenzyme A transporter 1

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Macromolecule #2: N-[1-(2-{methyl[2-(4-methylphenoxy)ethyl]amino}-2-oxoethyl)-1H-py...

MacromoleculeName: N-[1-(2-{methyl[2-(4-methylphenoxy)ethyl]amino}-2-oxoethyl)-1H-pyrazol-4-yl]-3-phenoxypropanamide
type: ligand / ID: 2 / Number of copies: 1 / Formula: A1CTY
Molecular weightTheoretical: 436.504 Da

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Macromolecule #3: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 3 / Number of copies: 2 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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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

Concentration5 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
150.0 mMNaClSodium chloride
20.0 mMC4H11NO3.HClTris-HCl

Details: 150mM NaCl, 20mM Tris pH 8.0
GridModel: UltrAuFoil R0./1 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY / Support film - Film thickness: 10 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec. / Pretreatment - Atmosphere: OTHER / Pretreatment - Pressure: 0.026000000000000002 kPa
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 277.15 K / Instrument: HOMEMADE PLUNGER
DetailsProtin was solubilized in DDM-CHS, buffer exchanged to LMNG-CHS and reconstituted into nanodisc using MSP1D1 and lipids POPC DOPE PS

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
TemperatureMin: 70.0 K / Max: 77.0 K
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Digitization - Dimensions - Width: 4096 pixel / Digitization - Dimensions - Height: 4096 pixel / Number grids imaged: 4 / Number real images: 6468 / Average exposure time: 3.29 sec. / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 30.0 µm / Calibrated magnification: 189189 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 190000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 3119666
CTF correctionSoftware - Name: cryoSPARC (ver. 4.7.0) / Type: PHASE FLIPPING ONLY
Startup modelType of model: INSILICO MODEL / In silico model: Ab initio reconstruction
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.27 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.7.0) / Number images used: 457520
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.7.0)
Details: Ab initio reconstruction, heterogeneous refinement, homogeneous refinement
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.7.0) / Details: Non uniform refinement
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelChain - Chain ID: A / Chain - Source name: AlphaFold / Chain - Initial model type: in silico model
RefinementProtocol: RIGID BODY FIT / Overall B value: 180
Output model

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

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