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- PDB-9unx: Cryo-EM structure of human OAT1 in complex with olmesartan and br... -

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Basic information

Entry
Database: PDB / ID: 9unx
TitleCryo-EM structure of human OAT1 in complex with olmesartan and bromide ion.
ComponentsSolute carrier family 22 member 6
KeywordsMEMBRANE PROTEIN / drug-drug interaction / transporter / substrate / organic anion.
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 / solute:inorganic anion antiporter activity ...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 / solute:inorganic anion antiporter activity / organic anion transport / : / monoatomic anion transport / chloride ion binding / antiporter activity / xenobiotic transmembrane transporter activity / 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
BROMIDE ION / Olmesartan / Solute carrier family 22 member 6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.45 Å
AuthorsJeon, H.M. / Eun, J. / Kim, K.H. / Kim, Y.
Funding support Korea, Republic Of, 1items
OrganizationGrant numberCountry
National Research Foundation (NRF, Korea)NRF-2022R1A5A10313611 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
DepositionApr 24, 2025Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 5, 2025Provider: repository / Type: Initial release
Revision 1.1Nov 19, 2025Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Solute carrier family 22 member 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,3953
Polymers61,8691
Non-polymers5262
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
Details: human OAT1 in complex with olmesartan and bromide ion, adopting inward facing conformation and embedded in LMNG/CHS micelle
Source: (gene. exp.) Homo sapiens (human) / Cell: Epithelial / Gene: SLC22A6, OAT1, PAHT / Organ: Kidney / Plasmid: pEG BacMam / Cell line (production host): HEK293S GnTi- / Organ (production host): Kidney / Production host: Homo sapiens (human) / References: UniProt: Q4U2R8
#2: Chemical ChemComp-BR / BROMIDE ION


Mass: 79.904 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Br / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-OLM / Olmesartan


Mass: 446.502 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H26N6O3 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication*YM
Has ligand of interestY
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 OAT1 in complex with olmesartan and bromide / Type: COMPLEX
Details: human OAT1 in complex with olmesartan and, adopting inward facing conformation and embedded in LMNG/CHS micelle
Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.062 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human) / Cellular location: Plasma membrane / Organ: kidney
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293S GnTi- / Plasmid: pEG BacMam
Buffer solutionpH: 7.5
Details: 20 mM HEPES, 150 mM NaCl, 20 mM Na/K-tartrate, 0.0015% LMNG, 0.00015% CHS
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMsodium bromideNaBr1
220 mMHEPESC8H18N2O4S1
320 mMsodium potassium tartrateKNaC4H4O61
SpecimenConc.: 18 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: This sample is a complex formed by composition of human OAT1, Fab targeting C-terminus of human OAT1, and the substrate olmesartan, purified in bromide buffer.
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

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 3 / Num. of real images: 32271
Image scansWidth: 5760 / Height: 4092

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.4.1particle selection
2EPUimage acquisition
4cryoSPARC4.4.1CTF correction
7Coot0.9.8.5model fitting
9cryoSPARC4.4.1initial Euler assignment
11RELION5classification
12cryoSPARC4.4.13D reconstruction
13PHENIX1.20.1_4487model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 10849658
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.45 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 118678 / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT
Atomic model buildingPDB-ID: 9KLZ

9klz


Pdb chain-ID: A / Accession code: 9KLZ / Source name: PDB / Type: experimental model
RefinementHighest resolution: 3.45 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0033735
ELECTRON MICROSCOPYf_angle_d0.4925084
ELECTRON MICROSCOPYf_dihedral_angle_d16.021323
ELECTRON MICROSCOPYf_chiral_restr0.035587
ELECTRON MICROSCOPYf_plane_restr0.005633

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