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- EMDB-62400: Cryo-EM strucuture of human OAT1 in complex with probenecid -

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Basic information

Entry
Database: EMDB / ID: EMD-62400
TitleCryo-EM strucuture of human OAT1 in complex with probenecid
Map data
Sample
  • Complex: human OAT1 in complex with probenecid
    • Protein or peptide: Solute carrier family 22 member 6
  • Ligand: 4-(dipropylsulfamoyl)benzoic acid
  • Ligand: CHLORIDE ION
Keywordsmembrane transporter / antiporter / gout / drug-drug interaction / drug elimination / MEMBRANE PROTEIN
Function / homology
Function and homology information


renal tubular secretion / alpha-ketoglutarate transport / alpha-ketoglutarate transmembrane transporter activity / Organic anion transport by SLC22 transporters / sodium-independent organic anion transport / : / metanephric proximal tubule development / prostaglandin transport / prostaglandin transmembrane transporter activity / organic anion transport ...renal tubular secretion / alpha-ketoglutarate transport / alpha-ketoglutarate transmembrane transporter activity / Organic anion transport by SLC22 transporters / sodium-independent organic anion transport / : / metanephric proximal tubule development / prostaglandin transport / prostaglandin transmembrane transporter activity / organic anion transport / solute:inorganic anion antiporter activity / : / monoatomic anion transport / chloride ion binding / antiporter activity / transmembrane transporter activity / xenobiotic transmembrane transporter activity / basal plasma membrane / caveola / basolateral plasma membrane / protein-containing complex / extracellular exosome / identical protein binding / plasma membrane
Similarity search - Function
Organic cation transport protein/SVOP / Major facilitator, sugar transporter-like / Sugar (and other) transporter / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily
Similarity search - Domain/homology
Solute carrier family 22 member 6
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.33 Å
AuthorsJeon HM / Eun J / Kim Y
Funding support Korea, Republic Of, 1 items
OrganizationGrant numberCountry
National Research Foundation (NRF, Korea)NRF-2022R1A5A103136112 Korea, Republic Of
CitationJournal: Structure / Year: 2025
Title: Cryo-EM structures of human OAT1 reveal drug binding and inhibition mechanisms.
Authors: Hyung-Min Jeon / Jisung Eun / Kelly H Kim / Youngjin Kim /
Abstract: The organic anion transporter 1 (OAT1) plays a key role in excreting waste from organic drug metabolism and contributes significantly to drug-drug interactions and drug disposition. However, the ...The organic anion transporter 1 (OAT1) plays a key role in excreting waste from organic drug metabolism and contributes significantly to drug-drug interactions and drug disposition. However, the structural basis of specific substrate and inhibitor transport by human OAT1 (hOAT1) has remained elusive. We determined four cryogenic electron microscopy (cryo-EM) structures of hOAT1 in its inward-facing conformation: the apo form, the substrate (olmesartan)-bound form with different anions, and the inhibitor (probenecid)-bound form. Structural and functional analyses revealed that Ser203 has an auxiliary role in chloride coordination, and it is a critical residue modulating olmesartan transport via chloride ion interactions. Structural comparisons indicate that inhibitors not only compete with substrates, but also obstruct substrate exit and entry from the cytoplasmic side, thereby increasing inhibitor retention. The findings can support drug development by providing insights into substrate recognition and the mechanism by which inhibitors arrest the OAT1 transport cycle.
History
DepositionNov 14, 2024-
Header (metadata) releaseNov 5, 2025-
Map releaseNov 5, 2025-
UpdateNov 5, 2025-
Current statusNov 5, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_62400.png

Downloads & links

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Map

FileDownload / File: emd_62400.map.gz / Format: CCP4 / Size: 129.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.81 Å/pix.
x 324 pix.
= 262.44 Å		0.81 Å/pix.
x 324 pix.
= 262.44 Å		0.81 Å/pix.
x 324 pix.
= 262.44 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.81 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.15
Minimum - Maximum-0.5855811 - 0.91087896
Average (Standard dev.)0.00019767862 (±0.015329444)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions324324324
Spacing324324324
CellA=B=C: 262.44 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_62400_msk_1.map
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AxesZYX

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Half map: #1

Fileemd_62400_half_map_1.map
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Half map: #2

Fileemd_62400_half_map_2.map
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Sample components

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Entire : human OAT1 in complex with probenecid

EntireName: human OAT1 in complex with probenecid
Components
  • Complex: human OAT1 in complex with probenecid
    • Protein or peptide: Solute carrier family 22 member 6
  • Ligand: 4-(dipropylsulfamoyl)benzoic acid
  • Ligand: CHLORIDE ION

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Supramolecule #1: human OAT1 in complex with probenecid

SupramoleculeName: human OAT1 in complex with probenecid / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Details: human OAT1 in complex with probenecid, adopting Inward-facing conformation and embedded in LMNG/CHS micelle.
Source (natural)Organism: Homo sapiens (human) / Tissue: Kidney / Location in cell: Plasma membrane
Molecular weightTheoretical: 62 KDa

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Macromolecule #1: Solute carrier family 22 member 6

MacromoleculeName: Solute carrier family 22 member 6 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 61.869027 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAFNDLLQQV GGVGRFQQIQ VTLVVLPLLL MASHNTLQNF TAAIPTHHCR PPADANLSKN GGLEVWLPRD RQGQPESCLR FTSPQWGLP FLNGTEANGT GATEPCTDGW IYDNSTFPST IVTEWDLVCS HRALRQLAQS LYMVGVLLGA MVFGYLADRL G RRKVLILN ...String:
MAFNDLLQQV GGVGRFQQIQ VTLVVLPLLL MASHNTLQNF TAAIPTHHCR PPADANLSKN GGLEVWLPRD RQGQPESCLR FTSPQWGLP FLNGTEANGT GATEPCTDGW IYDNSTFPST IVTEWDLVCS HRALRQLAQS LYMVGVLLGA MVFGYLADRL G RRKVLILN YLQTAVSGTC AAFAPNFPIY CAFRLLSGMA LAGISLNCMT LNVEWMPIHT RACVGTLIGY VYSLGQFLLA GV AYAVPHW RHLQLLVSAP FFAFFIYSWF FIESARWHSS SGRLDLTLRA LQRVARINGK REEGAKLSME VLRASLQKEL TMG KGQASA MELLRCPTLR HLFLCLSMLW FATSFAYYGL VMDLQGFGVS IYLIQVIFGA VDLPAKLVGF LVINSLGRRP AQMA ALLLA GICILLNGVI PQDQSIVRTS LAVLGKGCLA ASFNCIFLYT GELYPTMIRQ TGMGMGSTMA RVGSIVSPLV SMTAE LYPS MPLFIYGAVP VAASAVTVLL PETLGQPLPD TVQDLESRWA PTQKEAGIYP RKGKQTRQQQ EHQKYMVPLQ ASAQEK NGL

UniProtKB: Solute carrier family 22 member 6

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Macromolecule #2: 4-(dipropylsulfamoyl)benzoic acid

MacromoleculeName: 4-(dipropylsulfamoyl)benzoic acid / type: ligand / ID: 2 / Number of copies: 1 / Formula: RTO
Molecular weightTheoretical: 285.359 Da
Chemical component information

ChemComp-RTO:
4-(dipropylsulfamoyl)benzoic acid

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Macromolecule #3: CHLORIDE ION

MacromoleculeName: CHLORIDE ION / type: ligand / ID: 3 / Number of copies: 1 / Formula: CL
Molecular weightTheoretical: 35.453 Da

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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

Concentration15 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
200.0 mMNaClsoduium chloride
20.0 mMC8H18N2O4SHEPES

Details: 20 mM HEPES, 200 mM NaCl, 0.0015% LMNG, 0.00015% CHS
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec. / Pretreatment - Pressure: 0.025 kPa
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 283 K / Instrument: FEI VITROBOT MARK IV
Detailsthis sample is a complex formed by composition of human OAT1, Fab targetting C-terminus of HsOAT1, and the inhibitor probenecid.

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Digitization - Dimensions - Width: 4096 pixel / Digitization - Dimensions - Height: 4096 pixel / Number grids imaged: 2 / Number real images: 22975 / Average electron dose: 52.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 96000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 8145000
CTF correctionSoftware - Name: cryoSPARC (ver. 3.1.4) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.33 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.1.4) / Number images used: 97785
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.1.4)
Final angle assignmentType: NOT APPLICABLE
Final 3D classificationNumber classes: 8 / Avg.num./class: 91119 / Software - Name: RELION (ver. 4.0)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

8sdz


Chain - Chain ID: A / Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-9kl5:
Cryo-EM strucuture of human OAT1 in complex with probenecid

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