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- EMDB-40355: Structure of rat organic anion transporter 1 (OAT1) in complex wi... -

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Basic information

Entry
Database: EMDB / ID: EMD-40355
TitleStructure of rat organic anion transporter 1 (OAT1) in complex with probenecid
Map data
Sample
  • Complex: Rat OAT1/probenecid complex solubilized in detergent LMNG
    • Protein or peptide: Solute carrier family 22 member 6
  • Ligand: 4-(dipropylsulfamoyl)benzoic acid
  • Ligand: water
Keywordsorganic anion transporter / OAT / SLC22 / drug transporter / probenecid / TRANSPORT PROTEIN
Function / homology
Function and homology information


Organic anion transport / renal tubular secretion / alpha-ketoglutarate transmembrane transporter activity / alpha-ketoglutarate transport / sodium-independent organic anion transmembrane transporter activity / sodium-independent organic anion transport / metanephric proximal tubule development / prostaglandin transport / prostaglandin transmembrane transporter activity / organic anion transport ...Organic anion transport / renal tubular secretion / alpha-ketoglutarate transmembrane transporter activity / alpha-ketoglutarate transport / sodium-independent organic anion transmembrane transporter activity / sodium-independent organic anion transport / metanephric proximal tubule development / prostaglandin transport / prostaglandin transmembrane transporter activity / organic anion transport / organic anion transmembrane transporter activity / solute:inorganic anion antiporter activity / monoatomic anion transport / antiporter activity / chloride ion binding / xenobiotic transmembrane transporter activity / transmembrane transporter activity / basal plasma membrane / caveola / response to organic cyclic compound / basolateral plasma membrane / protein-containing complex / 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 speciesRattus norvegicus (Norway rat)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.86 Å
AuthorsDou T / Jiang J
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI) United States
CitationJournal: Nat Struct Mol Biol / Year: 2023
Title: The substrate and inhibitor binding mechanism of polyspecific transporter OAT1 revealed by high-resolution cryo-EM.
Authors: Tongyi Dou / Tengfei Lian / Shi Shu / Yi He / Jiansen Jiang /
Abstract: Organic anion transporters (OATs) of the SLC22 family have crucial roles in the transport of organic anions, including metabolites and therapeutic drugs, and in transporter-mediated drug-drug ...Organic anion transporters (OATs) of the SLC22 family have crucial roles in the transport of organic anions, including metabolites and therapeutic drugs, and in transporter-mediated drug-drug interactions. In the kidneys, OATs facilitate the elimination of metabolic waste products and xenobiotics. However, their transport activities can lead to the accumulation of certain toxic compounds within cells, causing kidney damage. Moreover, OATs are important drug targets, because their inhibition modulates the elimination or retention of substrates linked to diseases. Despite extensive research on OATs, the molecular basis of their substrate and inhibitor binding remains poorly understood. Here we report the cryo-EM structures of rat OAT1 (also known as SLC22A6) and its complexes with para-aminohippuric acid and probenecid at 2.1, 2.8 and 2.9 Å resolution, respectively. Our findings reveal a highly conserved substrate binding mechanism for SLC22 transporters, wherein four aromatic residues form a cage to accommodate the polyspecific binding of diverse compounds.
History
DepositionApr 7, 2023-
Header (metadata) releaseOct 18, 2023-
Map releaseOct 18, 2023-
UpdateNov 22, 2023-
Current statusNov 22, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_40355.png

Downloads & links

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Map

FileDownload / File: emd_40355.map.gz / Format: CCP4 / Size: 15.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.83 Å
Density
Contour LevelBy AUTHOR: 0.01
Minimum - Maximum-0.033071697 - 0.05582047
Average (Standard dev.)0.000017965134 (±0.0022321902)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions160160160
Spacing160160160
CellA=B=C: 132.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_40355_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_40355_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_40355_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : Rat OAT1/probenecid complex solubilized in detergent LMNG

EntireName: Rat OAT1/probenecid complex solubilized in detergent LMNG
Components
  • Complex: Rat OAT1/probenecid complex solubilized in detergent LMNG
    • Protein or peptide: Solute carrier family 22 member 6
  • Ligand: 4-(dipropylsulfamoyl)benzoic acid
  • Ligand: water

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Supramolecule #1: Rat OAT1/probenecid complex solubilized in detergent LMNG

SupramoleculeName: Rat OAT1/probenecid complex solubilized in detergent LMNG
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 61 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: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 60.816836 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAFNDLLKQV GGVGRFQLIQ VTMVVAPLLL MASHNTLQNF TAAIPPHHCR PPANANLSKD GGLEAWLPLD KQGQPESCLR FTSPQWGPP FYNGTEANGT RVTEPCIDGW VYDNSTFPST IVTEWNLVCS HRAFRQLAQS LYMVGVLLGA MVFGYLADRL G RRKVLILN ...String:
MAFNDLLKQV GGVGRFQLIQ VTMVVAPLLL MASHNTLQNF TAAIPPHHCR PPANANLSKD GGLEAWLPLD KQGQPESCLR FTSPQWGPP FYNGTEANGT RVTEPCIDGW VYDNSTFPST IVTEWNLVCS HRAFRQLAQS LYMVGVLLGA MVFGYLADRL G RRKVLILN YLQTAVSGTC AAYAPNYTVY CVFRLLSGMS LASIAINCMT LNVEWMPIHT RAYVGTLIGY VYSLGQFLLA GI AYAVPHW RHLQLVVSVP FFIAFIYSWF FIESARWYSS SGRLDLTLRA LQRVARINGK QEEGAKLSIE VLRTSLQKEL TLS KGQASA MELLRCPTLR HLFLCLSMLW FATSFAYYGL VMDLQGFGVS MYLIQVIFGA VDLPAKFVCF LVINSMGRRP AQMA SLLLA GICILVNGII PKSHTIIRTS LAVLGKGCLA SSFNCIFLYT GELYPTVIRQ TGLGMGSTMA RVGSIVSPLV SMTAE FYPS MPLFIFGAVP VVASAVTALL PETLGQPLPD TVQDLKSRSR GKQNQQQQEQ QKQMMPLQAS TQEKNGL

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: water

MacromoleculeName: water / type: ligand / ID: 3 / Number of copies: 22 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER / Water

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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

BufferpH: 8
Details: TBS buffer (20 mM Tris-HCl, 150 mM NaCl, pH 8.0) with 0.01% LMNG
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.0 mm / Nominal defocus max: 3.0 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 105000
Specialist opticsEnergy filter - Name: GIF Quantum LS / Energy filter - Slit width: 20 eV
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number real images: 4160 / Average exposure time: 6.25 sec. / Average electron dose: 60.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Details: The 3D reconstruction of apo rat OAT1 was used as the startup model
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software: (Name: RELION, cryoSPARC)
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.86 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 73688
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: AB INITIO MODEL
Output model

PDB-8sdz:
Structure of rat organic anion transporter 1 (OAT1) in complex with probenecid

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