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Structure paper

TitleCyclosporine A sterically inhibits statin transport by solute carrier OATP1B1.
Journal, issue, pagesJ Biol Chem, Vol. 301, Issue 5, Page 108484, Year 2025
Publish dateApr 6, 2025
AuthorsMin 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 /
PubMed AbstractMembers 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.
External linksJ Biol Chem / PubMed:40199401 / PubMed Central
MethodsEM (single particle)
Resolution3.15 - 3.41 Å
Structure data

46004

9cy1

EMDB-46004, PDB-9cy1:
Outward-facing OATP1B1 bound to sybody Sb5
Method: EM (single particle) / Resolution: 3.15 Å

46005

9cy3

EMDB-46005, PDB-9cy3:
Outward-facing Atorvastatin-bound OATP1B1 with sybody Sb5
Method: EM (single particle) / Resolution: 3.2 Å

46006

9cy4

EMDB-46006, PDB-9cy4:
Outward-facing cyclosporine A-bound OATP1B1 with sybody 5 (Sb5)
Method: EM (single particle) / Resolution: 3.41 Å

Chemicals

ChemComp-117:
7-[2-(4-FLUORO-PHENYL)-5-ISOPROPYL-3-PHENYL-4-PHENYLCARBAMOYL-PYRROL-1-YL]- 3,5-DIHYDROXY-HEPTANOIC ACID / medication*YM

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsTRANSPORT PROTEIN / solute carrier / sybody / membrane protein / drug-drug interactions

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