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- EMDB-17677: Human OATP1B1 -

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Basic information

Entry
Database: EMDB / ID: EMD-17677
TitleHuman OATP1B1
Map dataE1S-bound Human OATP1B1 with Fab18
Sample
  • Complex: Human OATP1B1
    • Complex: Solute carrier organic anion transporter family member 1B1
      • Protein or peptide: Solute carrier organic anion transporter family member 1B1
    • Complex: Fab18 (variable region)
      • Protein or peptide: Fab18 (heavy chain, variable region)
      • Protein or peptide: Fab18 (light chain, variable region)
  • Ligand: estrone 3-sulfate
  • Ligand: CHOLESTEROL HEMISUCCINATE
Keywordsorganic anion / E1S / E-3-S / estrone-3-sulphate / SLCO1B1 / uptake / drug / transporter / polypeptide / liver / hepatocyte / TRANSPORT PROTEIN
Function / homology
Function and homology information


Defective SLCO1B1 causes hyperbilirubinemia, Rotor type (HBLRR) / Transport of organic anions / sodium-independent organic anion transport / sodium-independent organic anion transmembrane transporter activity / thyroid hormone transmembrane transporter activity / prostaglandin transmembrane transporter activity / Atorvastatin ADME / organic anion transport / heme catabolic process / organic anion transmembrane transporter activity ...Defective SLCO1B1 causes hyperbilirubinemia, Rotor type (HBLRR) / Transport of organic anions / sodium-independent organic anion transport / sodium-independent organic anion transmembrane transporter activity / thyroid hormone transmembrane transporter activity / prostaglandin transmembrane transporter activity / Atorvastatin ADME / organic anion transport / heme catabolic process / organic anion transmembrane transporter activity / bile acid 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 / basolateral plasma membrane / 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 1B1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.6 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 20, 2023-
Header (metadata) releaseSep 27, 2023-
Map releaseSep 27, 2023-
UpdateMar 20, 2024-
Current statusMar 20, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_17677.png

Downloads & links

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Map

FileDownload / File: emd_17677.map.gz / Format: CCP4 / Size: 421.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationE1S-bound Human OATP1B1 with Fab18
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.51 Å/pix.
x 480 pix.
= 244.8 Å		0.51 Å/pix.
x 480 pix.
= 244.8 Å		0.51 Å/pix.
x 480 pix.
= 244.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.51 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.128
Minimum - Maximum-0.0018009443 - 1.9770203
Average (Standard dev.)0.0009635592 (±0.02181488)
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: E1S-bound Human OATP1B1 with Fab18 (half-map B)

Fileemd_17677_half_map_1.map
AnnotationE1S-bound Human OATP1B1 with Fab18 (half-map B)
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: E1S-bound Human OATP1B1 with Fab18 (half-map A)

Fileemd_17677_half_map_2.map
AnnotationE1S-bound Human OATP1B1 with Fab18 (half-map A)
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 OATP1B1

EntireName: Human OATP1B1
Components
  • Complex: Human OATP1B1
    • Complex: Solute carrier organic anion transporter family member 1B1
      • Protein or peptide: Solute carrier organic anion transporter family member 1B1
    • Complex: Fab18 (variable region)
      • Protein or peptide: Fab18 (heavy chain, variable region)
      • Protein or peptide: Fab18 (light chain, variable region)
  • Ligand: estrone 3-sulfate
  • Ligand: CHOLESTEROL HEMISUCCINATE

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Supramolecule #1: Human OATP1B1

SupramoleculeName: Human OATP1B1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Molecular weightTheoretical: 180 KDa

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Supramolecule #2: Solute carrier organic anion transporter family member 1B1

SupramoleculeName: Solute carrier organic anion transporter family member 1B1
type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: Fab18 (variable region)

SupramoleculeName: Fab18 (variable region) / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Solute carrier organic anion transporter family member 1B1

MacromoleculeName: Solute carrier organic anion transporter family member 1B1
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 76.519438 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDQNQHLNKT AEAQPSENKK TRYCNGLKMF LAALSLSFIA KTLGAIIMKS SIIHIERRFE ISSSLVGFID GSFEIGNLLV IVFVSYFGS KLHRPKLIGI GCFIMGIGGV LTALPHFFMG YYRYSKETNI NSSENSTSTL STCLINQILS LNRASPEIVG K GCLKESGS ...String:
MDQNQHLNKT AEAQPSENKK TRYCNGLKMF LAALSLSFIA KTLGAIIMKS SIIHIERRFE ISSSLVGFID GSFEIGNLLV IVFVSYFGS KLHRPKLIGI GCFIMGIGGV LTALPHFFMG YYRYSKETNI NSSENSTSTL STCLINQILS LNRASPEIVG K GCLKESGS YMWIYVFMGN MLRGIGETPI VPLGLSYIDD FAKEGHSSLY LGILNAIAMI GPIIGFTLGS LFSKMYVDIG YV DLSTIRI TPTDSRWVGA WWLNFLVSGL FSIISSIPFF FLPQTPNKPQ KERKASLSLH VLETNDEKDQ TANLTNQGKN ITK NVTGFF QSFKSILTNP LYVMFVLLTL LQVSSYIGAF TYVFKYVEQQ YGQPSSKANI LLGVITIPIF ASGMFLGGYI IKKF KLNTV GIAKFSCFTA VMSLSFYLLY FFILCENKSV AGLTMTYDGN NPVTSHRDVP LSYCNSDCNC DESQWEPVCG NNGIT YISP CLAGCKSSSG NKKPIVFYNC SCLEVTGLQN RNYSAHLGEC PRDDACTRKF YFFVAIQVLN LFFSALGGTS HVMLIV KIV QPELKSLALG FHSMVIRALG GILAPIYFGA LIDTTCIKWS TNNCGTRGSC RTYNSTSFSR VYLGLSSMLR VSSLVLY II LIYAMKKKYQ EKDINASENG SVMDEANLES LNKNKHFVPS AGADSETHC

UniProtKB: Solute carrier organic anion transporter family member 1B1

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Macromolecule #2: Fab18 (heavy chain, variable region)

MacromoleculeName: Fab18 (heavy chain, variable region) / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.374008 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: EISEVQLVES GGGLVQPGGS LRLSCAASGF NFSSSSIHWV RQAPGKGLEW VASISSSSGS TSYADSVKGR FTISADTSKN TAYLQMNSL RAEDTAVYYC ARYGWGGPWY YWLRDSRSGI DYWGQGTLVT VSSASTKGPS VSGGTAALGC LVKDYFPEPV T VSWNSGAL ...String:
EISEVQLVES GGGLVQPGGS LRLSCAASGF NFSSSSIHWV RQAPGKGLEW VASISSSSGS TSYADSVKGR FTISADTSKN TAYLQMNSL RAEDTAVYYC ARYGWGGPWY YWLRDSRSGI DYWGQGTLVT VSSASTKGPS VSGGTAALGC LVKDYFPEPV T VSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL GTQTYICNVN HKPSNTKVDK KVEPKSCDKT HT

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Macromolecule #3: Fab18 (light chain, variable region)

MacromoleculeName: Fab18 (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: estrone 3-sulfate

MacromoleculeName: estrone 3-sulfate / type: ligand / ID: 4 / Number of copies: 1 / Formula: FY5
Molecular weightTheoretical: 350.429 Da
Chemical component information

ChemComp-FY5:
estrone 3-sulfate / medication, hormone*YM

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Macromolecule #5: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 5 / Number of copies: 1 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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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

Concentration0.22 mg/mL
BufferpH: 7.4
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 60.5 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / 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
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 104547
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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