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- EMDB-17655: Human OATP1B3 -

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Basic information

Entry
Database: EMDB / ID: EMD-17655
TitleHuman OATP1B3
Map databicarbonate-bound OATP1B3 with Fab19
Sample
  • Complex: Human OATP1B3
    • Protein or peptide: Solute carrier organic anion transporter family member 1B3
    • Protein or peptide: Fab19 (heavy chain, variable region)
    • Protein or peptide: Fab19 (light chain, variable region)
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: BICARBONATE IONBicarbonate
  • Ligand: CHOLESTEROL
Keywordsorganic anion / bicarbonate / SLCO1B3 / uptake / drug / transporter / polypeptide / liver / TRANSPORT PROTEIN
Function / homology
Function and homology information


Defective SLCO1B3 causes hyperbilirubinemia, Rotor type (HBLRR) / Transport of organic anions / sodium-independent organic anion transmembrane transporter activity / sodium-independent organic anion transport / negative regulation of peptidase activity / bile acid transmembrane transporter activity / organic anion transport / heme catabolic process / Atorvastatin ADME / organic anion transmembrane transporter activity ...Defective SLCO1B3 causes hyperbilirubinemia, Rotor type (HBLRR) / Transport of organic anions / sodium-independent organic anion transmembrane transporter activity / sodium-independent organic anion transport / negative regulation of peptidase activity / bile acid transmembrane transporter activity / organic anion transport / heme catabolic process / Atorvastatin ADME / organic anion transmembrane transporter activity / bile acid and bile salt transport / Heme degradation / monoatomic ion transport / Recycling of bile acids and salts / xenobiotic metabolic process / basal plasma membrane / serine-type endopeptidase inhibitor activity / basolateral plasma membrane / plasma membrane
Similarity search - Function
Organic anion transporter polypeptide / Organic Anion Transporter Polypeptide (OATP) family / Kazal-type serine protease inhibitor domain / Kazal domain superfamily / Kazal domain / Kazal domain profile. / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily
Similarity search - Domain/homology
Solute carrier organic anion transporter family member 1B3
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.97 Å
AuthorsCiuta A-D / Nosol K / Kowal J / Mukherjee S / Ramirez AS / Stieger B / Kossiakoff AA / Locher KP
Funding support Switzerland, United States, 2 items
OrganizationGrant numberCountry
Swiss National Science Foundation310030_189111 Switzerland
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM117372 United States
CitationJournal: Nat Commun / Year: 2023
Title: Structure of human drug transporters OATP1B1 and OATP1B3.
Authors: Anca-Denise Ciută / Kamil Nosol / Julia Kowal / Somnath Mukherjee / Ana S Ramírez / Bruno Stieger / Anthony A Kossiakoff / Kaspar P Locher /
Abstract: The organic anion transporting polypeptides OATP1B1 and OATP1B3 are membrane proteins that mediate uptake of drugs into the liver for subsequent conjugation and biliary excretion, a key step in drug ...The organic anion transporting polypeptides OATP1B1 and OATP1B3 are membrane proteins that mediate uptake of drugs into the liver for subsequent conjugation and biliary excretion, a key step in drug elimination from the human body. Polymorphic variants of these transporters can cause reduced drug clearance and adverse drug effects such as statin-induced rhabdomyolysis, and co-administration of OATP substrates can lead to damaging drug-drug interaction. Despite their clinical relevance in drug disposition and pharmacokinetics, the structure and mechanism of OATPs are unknown. Here we present cryo-EM structures of human OATP1B1 and OATP1B3 bound to synthetic Fab fragments and in functionally distinct states. A single estrone-3-sulfate molecule is bound in a pocket located in the C-terminal half of OATP1B1. The shape and chemical nature of the pocket rationalize the preference for diverse organic anions and allow in silico docking of statins. The structure of OATP1B3 is determined in a drug-free state but reveals a bicarbonate molecule bound to the conserved signature motif and a histidine residue that is prevalent in OATPs exhibiting pH-dependent activity.
History
DepositionJun 17, 2023-
Header (metadata) releaseSep 27, 2023-
Map releaseSep 27, 2023-
UpdateSep 27, 2023-
Current statusSep 27, 2023Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_17655.png

Downloads & links

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Map

FileDownload / File: emd_17655.map.gz / Format: CCP4 / Size: 421.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationbicarbonate-bound OATP1B3 with Fab19
Voxel sizeX=Y=Z: 0.51 Å
Density
Contour LevelBy AUTHOR: 0.005
Minimum - Maximum-0.015209728 - 0.024013504
Average (Standard dev.)-0.000006864759 (±0.00069441384)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions480480480
Spacing480480480
CellA=B=C: 244.79999 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: bicarbonate-bound OATP1B3 with Fab19 (half-map 1)

Fileemd_17655_half_map_1.map
Annotationbicarbonate-bound OATP1B3 with Fab19 (half-map 1)
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: bicarbonate-bound OATP1B3 with Fab19 (half-map 2)

Fileemd_17655_half_map_2.map
Annotationbicarbonate-bound OATP1B3 with Fab19 (half-map 2)
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human OATP1B3

EntireName: Human OATP1B3
Components
  • Complex: Human OATP1B3
    • Protein or peptide: Solute carrier organic anion transporter family member 1B3
    • Protein or peptide: Fab19 (heavy chain, variable region)
    • Protein or peptide: Fab19 (light chain, variable region)
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: BICARBONATE IONBicarbonate
  • Ligand: CHOLESTEROL

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Supramolecule #1: Human OATP1B3

SupramoleculeName: Human OATP1B3 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 180 KDa

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Macromolecule #1: Solute carrier organic anion transporter family member 1B3

MacromoleculeName: Solute carrier organic anion transporter family member 1B3
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 77.478586 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDQHQHLNKT AESASSEKKK TRRCNGFKMF LAALSFSYIA KALGGIIMKI SITQIERRFD ISSSLAGLID GSFEIGNLLV IVFVSYFGS KLHRPKLIGI GCLLMGTGSI LTSLPHFFMG YYRYSKETHI NPSENSTSSL STCLINQTLS FNGTSPEIVE K DCVKESGS ...String:
MDQHQHLNKT AESASSEKKK TRRCNGFKMF LAALSFSYIA KALGGIIMKI SITQIERRFD ISSSLAGLID GSFEIGNLLV IVFVSYFGS KLHRPKLIGI GCLLMGTGSI LTSLPHFFMG YYRYSKETHI NPSENSTSSL STCLINQTLS FNGTSPEIVE K DCVKESGS HMWIYVFMGN MLRGIGETPI VPLGISYIDD FAKEGHSSLY LGSLNAIGMI GPVIGFALGS LFAKMYVDIG YV DLSTIRI TPKDSRWVGA WWLGFLVSGL FSIISSIPFF FLPKNPNKPQ KERKISLSLH VLKTNDDRNQ TANLTNQGKN VTK NVTGFF QSLKSILTNP LYVIFLLLTL LQVSSFIGSF TYVFKYMEQQ YGQSASHANF LLGIITIPTV ATGMFLGGFI IKKF KLSLV GIAKFSFLTS MISFLFQLLY FPLICESKSV AGLTLTYDGN NSVASHVDVP LSYCNSECNC DESQWEPVCG NNGIT YLSP CLAGCKSSSG IKKHTVFYNC SCVEVTGLQN RNYSAHLGEC PRDNTCTRKF FIYVAIQVIN SLFSATGGTT FILLTV KIV QPELKALAMG FQSMVIRTLG GILAPIYFGA LIDKTCMKWS TNSCGAQGAC RIYNSVFFGR VYLGLSIALR FPALVLY IV FIFAMKKKFQ GKDTKASDNE RKVMDEANLE FLNNGEHFVP SAGTDSKTCN LDMQDNAAAN

UniProtKB: Solute carrier organic anion transporter family member 1B3

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Macromolecule #2: Fab19 (heavy chain, variable region)

MacromoleculeName: Fab19 (heavy chain, variable region) / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.599549 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: EISEVQLVES GGGLVQPGGS LRLSCAASGF NFSSSSIHWV RQAPGKGLEW VASISSSSGS TSYADSVKGR FTISADTSKN TAYLQMNSL RAEDTAVYYC ARYYIKRWWL MSWEDYSMGL DYWGQGTLVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC L VKDYFPEP ...String:
EISEVQLVES GGGLVQPGGS LRLSCAASGF NFSSSSIHWV RQAPGKGLEW VASISSSSGS TSYADSVKGR FTISADTSKN TAYLQMNSL RAEDTAVYYC ARYYIKRWWL MSWEDYSMGL DYWGQGTLVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC L VKDYFPEP VTVSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL GTQTYICNVN HKPSNTKVDK KVEPKSCDKT HT

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Macromolecule #3: Fab19 (light chain, variable region)

MacromoleculeName: Fab19 (light chain, variable region) / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.258783 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: SDIQMTQSPS SLSASVGDRV TITCRASQSV SSAVAWYQQK PGKAPKLLIY SASSLYSGVP SRFSGSRSGT DFTLTISSLQ PEDFATYYC QQSSSSLITF GQGTKVEIKR TVAAPSVFIF PPSDSQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD ...String:
SDIQMTQSPS SLSASVGDRV TITCRASQSV SSAVAWYQQK PGKAPKLLIY SASSLYSGVP SRFSGSRSGT DFTLTISSLQ PEDFATYYC QQSSSSLITF GQGTKVEIKR TVAAPSVFIF PPSDSQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC

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Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 1 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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Macromolecule #5: BICARBONATE ION

MacromoleculeName: BICARBONATE ION / type: ligand / ID: 5 / Number of copies: 1 / Formula: BCT
Molecular weightTheoretical: 61.017 Da
Chemical component information

ChemComp-BCT:
BICARBONATE ION / pH buffer*YM / Bicarbonate

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Macromolecule #6: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 6 / Number of copies: 3 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL / Cholesterol

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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

Concentration0.59 mg/mL
BufferpH: 7.4
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.6 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 60.5 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.97 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 75610
FSC plot (resolution estimation)

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