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- PDB-9cy3: Outward-facing Atorvastatin-bound OATP1B1 with sybody Sb5 -

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Basic information

Entry
Database: PDB / ID: 9cy3
TitleOutward-facing Atorvastatin-bound OATP1B1 with sybody Sb5
Components
  • Solute carrier organic anion transporter family member 1B1
  • Sybody 5
KeywordsTRANSPORT PROTEIN / solute carrier / sybody / membrane protein / drug-drug interactions
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 / organic anion transport / heme catabolic process / organic anion transmembrane transporter activity / Atorvastatin ADME ...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 / organic anion transport / heme catabolic process / organic anion transmembrane transporter activity / Atorvastatin ADME / bile acid transmembrane transporter activity / Heme degradation / bile acid and bile salt transport / Recycling of bile acids and salts / monoatomic ion transport / 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
Chem-117 / Solute carrier organic anion transporter family member 1B1
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsSung, M.W. / Lees, J.A. / Han, S.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J Biol Chem / Year: 2025
Title: Cyclosporine A sterically inhibits statin transport by solute carrier OATP1B1.
Authors: Min Woo Sung / Kuan Hu / Lea M Hurlimann / Joshua A Lees / Kimberly F Fennell / Mark A West / Chester Costales / Amilcar David Rodrigues / Iwan Zimmermann / Roger J P Dawson / Shenping Liu / Seungil Han /
Abstract: Members of the Organic Anion Transporter Polypeptides (OATP) are integral membrane proteins responsible for facilitating the transport of organic anions across the cell membrane. OATP1B1 (SLCO1B1), ...Members of the Organic Anion Transporter Polypeptides (OATP) are integral membrane proteins responsible for facilitating the transport of organic anions across the cell membrane. OATP1B1 (SLCO1B1), the prototypic OATP family member, is the most abundant uptake transporter in the liver and a key mediator of the hepatic uptake and clearance of numerous endogenous and xenobiotic compounds. It serves as a locus of important drug-drug interactions, such as those between statins and cyclosporine A, and carries the potential to enable liver-targeting therapeutics. In this study, we report cryo-EM structures of OATP1B1 and its complexes with one of its statin substrates, atorvastatin, and an inhibitor, cyclosporine A. This structural analysis has yielded insights into the mechanisms underlying the OATP1B1-mediated transport of statins and the inhibitory effect of cyclosporine A. These findings contribute to a better understanding of the molecular processes involved in drug transport and offer potential avenues for the development of targeted medications for liver-related conditions.
History
DepositionAug 1, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 16, 2025Provider: repository / Type: Initial release
Revision 1.0Apr 16, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Apr 16, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Apr 16, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Apr 16, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Apr 23, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.2May 14, 2025Group: Data collection / Database references / Category: citation / em_admin / em_software
Item: _citation.journal_volume / _em_admin.last_update / _em_software.name

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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 1B1
B: Sybody 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)96,3253
Polymers95,7662
Non-polymers5591
Water00
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

#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: 79880.977 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: Protein Sybody 5


Mass: 15885.510 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli)
#3: Chemical ChemComp-117 / 7-[2-(4-FLUORO-PHENYL)-5-ISOPROPYL-3-PHENYL-4-PHENYLCARBAMOYL-PYRROL-1-YL]- 3,5-DIHYDROXY-HEPTANOIC ACID / ATORVASTATIN


Mass: 558.640 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H35FN2O5 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication*YM
Has ligand of interestY
Has protein modificationY

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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: Outward-facing atorvastatin-bound OATP1B1 with Sybody 5
Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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
Image recordingElectron dose: 60 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 127971 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0055207
ELECTRON MICROSCOPYf_angle_d0.9187051
ELECTRON MICROSCOPYf_dihedral_angle_d5.677738
ELECTRON MICROSCOPYf_chiral_restr0.055786
ELECTRON MICROSCOPYf_plane_restr0.008878

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