Interaction of three regiospecific amino acid residues is required for OATP1B1 gain of OATP1B3 substrate specificity.

Molecular Pharmaceutics
Marianne K DeGorterRichard B Kim

Abstract

The human organic anion-transporting polypeptides OATP1B1 (SLCO1B1) and OATP1B3 (SLCO1B3) are liver-enriched membrane transporters of major importance to hepatic uptake of numerous endogenous compounds, including bile acids, steroid conjugates, hormones, and drugs, including the 3-hydroxy-3-methylglutaryl Co-A reductase inhibitor (statin) family of cholesterol-lowering compounds. Despite their remarkable substrate overlap, there are notable exceptions: in particular, the gastrointestinal peptide hormone cholecystokinin-8 (CCK-8) is a high affinity substrate for OATP1B3 but not OATP1B1. We utilized homologous recombination of linear DNA by E. coli to generate a library of cDNA containing monomer size chimeric OATP1B1-1B3 and OATP1B3-1B1 transporters with randomly distributed chimeric junctions to identify three discrete regions of the transporter involved in conferring CCK-8 transport activity. Site-directed mutagenesis of three key residues in OATP1B1 transmembrane helices 1 and 10, and extracellular loop 6, to the corresponding residues in OATP1B3, resulted in a gain of CCK-8 transport by OATP1B1. The residues appear specific to CCK-8, as the mutations did not affect transport of the shared OATP1B substrate atorvastatin or the...Continue Reading

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Citations

Mar 20, 2013·Molecular Aspects of Medicine·Bruno Hagenbuch, Bruno Stieger
Mar 7, 2013·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·B WilliamsonM G Soars
Nov 23, 2019·Endocrine Reviews·Stefan GroenewegW Edward Visser
Jun 10, 2021·Journal of Chemical Information and Modeling·Alzbeta TuerkovaBarbara Zdrazil
Aug 28, 2021·International Journal of Molecular Sciences·Yi-Hsueh LeeJong-Kai Hsiao
Dec 7, 2021·Frontiers in Pharmacology·Anne Michelli Reis SilveiraPatricia de Oliveira Carvalho

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