Structural characterization of the human organic anion transporter OATP2B1

Organic anion transporting polypeptides (OATPs), encoded by SLC21 / SLCO genes, are essential influx transporters responsible for the cellular uptake of diverse endogenous molecules and clinical drugs 1 , 2 , 3 . The OATP family comprises six subfamilies with distinct tissue distribution and substrate specificity, among which liver-enriched OATP1B1/1B3 and widely distributed OATP2B1 are the most pharmacologically critical isoforms 4 . Unlike OATP1B1/1B3 that primarily mediate hepatic drug clearance, OATP2B1 regulates both intestinal drug absorption and hepatic extraction, serving as a key mediator of food–drug and drug–drug interactions (DDIs) 5 , 6 . Accumulating evidence indicates that OATP2B1 inhibition contributes to unexplained alterations in systemic drug exposure beyond OATP1B1/1B3 modulation, highlighting its unique pharmacological importance 7 . Moreover, genetic variations in SLCO2B1 alter drug transport efficiency, leading to interindividual differences in drug response and adverse drug reactions 8 , 9 . Despite its functional significance, the lack of high-resolution structural information of OATP2B1 has hindered the mechanistic understanding of its substrate recognition, specificity, and conformational transport dynamics.