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- PDB-8pg0: Human OATP1B3 -

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Basic information

Entry
Database: PDB / ID: 8pg0
TitleHuman OATP1B3
Components
  • Fab19 (heavy chain, variable region)
  • Fab19 (light chain, variable region)
  • Solute carrier organic anion transporter family member 1B3
KeywordsTRANSPORT PROTEIN / organic anion / bicarbonate / SLCO1B3 / uptake / drug / transporter / polypeptide / liver
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
BICARBONATE ION / CHOLESTEROL / Solute carrier organic anion transporter family member 1B3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.97 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 17, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 27, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Solute carrier organic anion transporter family member 1B3
H: Fab19 (heavy chain, variable region)
L: Fab19 (light chain, variable region)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)127,7798
Polymers126,3373
Non-polymers1,4425
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Antibody , 2 types, 2 molecules HL

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


Mass: 25599.549 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 Fab19 (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)

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Protein / Sugars , 2 types, 2 molecules A

#1: Protein Solute carrier organic anion transporter family member 1B3 / Liver-specific organic anion transporter 2 / LST-2 / OATP1B3 / Organic anion transporter 8 / ...Liver-specific organic anion transporter 2 / LST-2 / OATP1B3 / Organic anion transporter 8 / Organic anion-transporting polypeptide 8 / OATP-8 / Solute carrier family 21 member 8


Mass: 77478.586 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLCO1B3, LST2, OATP1B3, OATP8, SLC21A8 / Production host: Homo sapiens (human) / References: UniProt: Q9NPD5
#4: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 2 types, 4 molecules

#5: Chemical ChemComp-BCT / BICARBONATE ION / Bicarbonate


Mass: 61.017 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: CHO3 / Feature type: SUBJECT OF INVESTIGATION / Comment: pH buffer*YM
#6: Chemical ChemComp-CLR / CHOLESTEROL / Cholesterol


Mass: 386.654 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C27H46O

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Details

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

ComponentName: Human OATP1B3 / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 0.18 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenConc.: 0.59 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 FIELDBright-field microscopy / 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: 2.97 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 75610 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0155961
ELECTRON MICROSCOPYf_angle_d1.1798080
ELECTRON MICROSCOPYf_dihedral_angle_d16.4742066
ELECTRON MICROSCOPYf_chiral_restr0.066926
ELECTRON MICROSCOPYf_plane_restr0.01968

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