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- PDB-8phw: Human OATP1B1 -

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Basic information

Entry
Database: PDB / ID: 8phw
TitleHuman OATP1B1
Components
  • Fab18 (heavy chain, variable region)
  • Fab18 (light chain, variable region)
  • Solute carrier organic anion transporter family member 1B1
KeywordsTRANSPORT PROTEIN / organic anion / E1S / E-3-S / estrone-3-sulphate / SLCO1B1 / uptake / drug / transporter / polypeptide / liver / hepatocyte
Function / homology
Function and homology information


Defective SLCO1B1 causes hyperbilirubinemia, Rotor type (HBLRR) / Transport of organic anions / sodium-independent organic anion transmembrane transporter activity / sodium-independent organic anion transport / thyroid hormone transmembrane transporter activity / bile acid transmembrane transporter activity / prostaglandin transmembrane transporter activity / organic anion transport / Atorvastatin ADME / organic anion transmembrane transporter activity ...Defective SLCO1B1 causes hyperbilirubinemia, Rotor type (HBLRR) / Transport of organic anions / sodium-independent organic anion transmembrane transporter activity / sodium-independent organic anion transport / thyroid hormone transmembrane transporter activity / bile acid transmembrane transporter activity / prostaglandin transmembrane transporter activity / organic anion transport / Atorvastatin ADME / organic anion transmembrane transporter activity / heme catabolic process / 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
estrone 3-sulfate / CHOLESTEROL HEMISUCCINATE / Solute carrier organic anion transporter family member 1B1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsCiuta, A.-D. / Nosol, K. / Kowal, J. / Mukherjee, S. / Ramirez, A.S. / Stieger, B. / Kossiakoff, A.A. / Locher, K.P.
Funding support Switzerland, United States, 2items
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, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 27, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 20, 2024Group: Database references / Structure summary / Category: em_entity_assembly / pdbx_database_related
Item: _em_entity_assembly.entity_id_list / _pdbx_database_related.content_type

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Solute carrier organic anion transporter family member 1B1
H: Fab18 (heavy chain, variable region)
L: Fab18 (light chain, variable region)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)124,9895
Polymers124,1523
Non-polymers8372
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 organic anion transporter family member 1B1 / SLCO1B1 / Liver-specific organic anion transporter 1 / LST-1 / OATP-C / Organic anion transporter ...SLCO1B1 / Liver-specific organic anion transporter 1 / LST-1 / OATP-C / Organic anion transporter SLC21A6 / Sodium-independent organic anion-transporting polypeptide 2 / OATP-2 / Solute carrier family 21 member 6


Mass: 76519.438 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLCO1B1, LST1, OATP1B1, OATP2, OATPC, SLC21A6 / Production host: Homo sapiens (human) / References: UniProt: Q9Y6L6
#2: Antibody Fab18 (heavy chain, variable region)


Mass: 24374.008 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#3: Antibody Fab18 (light chain, variable region)


Mass: 23258.783 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#4: Chemical ChemComp-FY5 / estrone 3-sulfate


Mass: 350.429 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H22O5S / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, hormone*YM
#5: Chemical ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H50O4
Has ligand of interestY

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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

Component
IDNameTypeEntity IDParent-IDSource
1Human OATP1B1COMPLEX#1-#30MULTIPLE SOURCES
2Solute carrier organic anion transporter family member 1B1COMPLEX#11RECOMBINANT
3Fab18 (variable region)COMPLEX#2-#31RECOMBINANT
Molecular weightValue: 0.18 MDa / Experimental value: YES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Escherichia coli (E. coli)562
Buffer solutionpH: 7.4
SpecimenConc.: 0.22 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 600 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 60.5 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 104547 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0045476
ELECTRON MICROSCOPYf_angle_d0.5767435
ELECTRON MICROSCOPYf_dihedral_angle_d12.6691918
ELECTRON MICROSCOPYf_chiral_restr0.041849
ELECTRON MICROSCOPYf_plane_restr0.005904

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