Molecular mechanisms for the activation of human organic anion transporting polypeptide 1B3 by quercetin-3-O-α-L-arabinopyranosyl(1 → 2)-α-L-rhamnopyranoside

Human organic anion transporting polypeptides (OATPs) 1B1 and 1B3 are two closely related transporters. However, OATP1B1- and 1B3-mediated estrone-3-sulfate (E3S) uptake can be differentially modulated by quercetin-3-O-α-L-arabinopyranosyl(1 → 2)-α-L-rhamnopyranoside (QAR), a compound found in some fruits such as jujube. In this study, we isolated QAR from jujube leaves and investigated the molecular mechanism underlying the activation of OATP1B3-mediated E3S uptake by QAR through functional characterization on a range of chimeric transporters derived from OATP1B3 and molecular modeling. Our findings revealed that the residue Ser545 in transmembrane domain 10 (TM10) is crucial for the activation of OATP1B3 by QAR. Kinetic analyses showed that QAR enhances OATP1B3-mediated E3S uptake at low substrate concentrations due to an increase in substrate binding affinity. Mutational analysis and molecular modeling suggested that amino acid residues with smaller side chains at position 545 are vital for the activation of OATP1B3, as bulkier residues could lead to steric collision with E3S. While QAR stimulates OATP1B3-mediated E3S uptake, it inhibits OATP1B3-mediated estradiol-17β-glucuronide/rosuvastatin uptake, indicating that the effect of QAR on OATP1B3's function is substrate-dependent. In summary, Ser545 within TM10 is essential for the activation of OATP1B3-mediated E3S uptake by QAR.

Chimera; Molecular modeling; OATP; Quercetin-3-O-α-L-arabinopyranosyl(1 → 2)-α-L-rhamnopyranoside; Transporter.