8HNC

Cryo-EM structure of human OATP1B1 in complex with bilirubin

Summary for 8HNC

• Entry DOI: 10.2210/pdb8hnc/pdb
• EMDB information: 34910
• Descriptor: Solute carrier organic anion transporter family member 1B1, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 3-[5-[(Z)-(4-ethenyl-3-methyl-5-oxidanylidene-pyrrol-2-ylidene)methyl]-2-[[5-[(Z)-(3-ethenyl-4-methyl-5-oxidanylidene-pyrrol-2-ylidene)methyl]-3-(3-hydroxy-3-oxopropyl)-4-methyl-1H-pyrrol-2-yl]methyl]-4-methyl-1H-pyrrol-3-yl]propanoic acid, ... (4 entities in total)
• Functional Keywords: transporter, oatp1b1, organic anion transporting peptide, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 80021.02

Authors

Shan, Z.,Yang, X.,Liu, H.,Nan, J.,Yuan, Y.,Zhang, Y. (deposition date: 2022-12-07, release date: 2023-09-13, Last modification date: 2024-11-13)

Primary citation

Shan, Z.,Yang, X.,Liu, H.,Yuan, Y.,Xiao, Y.,Nan, J.,Zhang, W.,Song, W.,Wang, J.,Wei, F.,Zhang, Y.
Cryo-EM structures of human organic anion transporting polypeptide OATP1B1.
Cell Res., 33:940-951, 2023

PubMed Abstract: Members of the solute carrier organic anion transporting polypeptide (OATPs) family function as transporters for a large variety of amphipathic organic anions including endogenous metabolites and clinical drugs, such as bile salts, steroids, thyroid hormones, statins, antibiotics, antivirals, and anticancer drugs. OATP1B1 plays a vital role in transporting such substances into the liver for hepatic clearance. FDA and EMA recommend conducting in vitro testing of drug-drug interactions (DDIs) involving OATP1B1. However, the structure and working mechanism of OATPs still remains elusive. In this study, we determined cryo-EM structures of human OATP1B1 bound with representative endogenous metabolites (bilirubin and estrone-3-sulfate), a clinical drug (simeprevir), and a fluorescent indicator (2',7'-dichlorofluorescein), in both outward- and inward-open states. These structures reveal major and minor substrate binding pockets and conformational changes during transport. In combination with mutagenesis studies and molecular dynamics simulations, our work comprehensively elucidates the transport mechanism of OATP1B1 and provides the structural basis for DDI predictions involving OATP1B1, which will greatly promote our understanding of OATPs.

PubMed: 37674011
DOI: 10.1038/s41422-023-00870-8

Experimental method

ELECTRON MICROSCOPY (3.73 Å)