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- PDB-9kkk: Cryo-EM structure of human SLC22A6 (OAT1) in the apo-state -

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Basic information

Entry
Database: PDB / ID: 9kkk
TitleCryo-EM structure of human SLC22A6 (OAT1) in the apo-state
ComponentsSolute carrier family 22 member 6
KeywordsMEMBRANE PROTEIN / Antiporter / Organic Anion / drug-drug interaction. nephrotoxicity
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.85 Å
AuthorsJeon, H.M. / Eun, J. / Kim, Y.
Funding support Korea, Republic Of, 1items
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 13, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 5, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Solute carrier family 22 member 6


Theoretical massNumber of molelcules
Total (without water)61,8691
Polymers61,8691
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Solute carrier family 22 member 6 / Organic anion transporter 1 / hOAT1 / PAH transporter / hPAHT / Renal organic anion transporter 1 / hROAT1


Mass: 61869.027 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC22A6, OAT1, PAHT / Cell line (production host): HEK293S GnTi- / Organ (production host): KIDNEY / Production host: Homo sapiens (human) / References: UniProt: Q4U2R8
Has protein modificationY

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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 Organic Anion Transporter 1 / Type: COMPLEX
Details: Human OAT1 in LMNG/GDN/CHS micelle, adopting inward-facing conformation.
Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.062 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: human embryonic kidney / Plasmid: pEG BacMam
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
1200 mMsodium chlorideNaCl1
220 mM4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acidHEPES1
SpecimenConc.: 9 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: 283 K

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Electron microscopy imaging

MicroscopyModel: TFS TALOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal magnification: 100000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN
Image recordingAverage exposure time: 40 sec. / Electron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 4 / Num. of real images: 25948
Image scansWidth: 4092 / Height: 5760

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Processing

EM software
IDNameVersionCategory
1cryoSPARC3.1.4particle selection
4cryoSPARC3.1.4CTF correction
7Coot0.9.8.5model fitting
9cryoSPARC3.1.4initial Euler assignment
11cryoSPARC3.1.4classification
12cryoSPARC3.1.43D reconstruction
13PHENIX1.20.1model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 17750625
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.85 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 255646 / Symmetry type: POINT
Atomic model buildingPDB-ID: 8SDU

8sdu


Pdb chain-ID: A / Accession code: 8SDU / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0033851
ELECTRON MICROSCOPYf_angle_d0.5795250
ELECTRON MICROSCOPYf_dihedral_angle_d3.444529
ELECTRON MICROSCOPYf_chiral_restr0.039615
ELECTRON MICROSCOPYf_plane_restr0.006660

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