Molecular basis of polyspecific drug binding and transport by OCT1 and OCT2

Abstract

A wide range of endogenous and xenobiotic organic ions require facilitated transport systems to cross the plasma membrane for their disposition. In mammals, organic cation transporter subtypes 1 and 2 (OCT1 and OCT2, also known as SLC22A1 and SLC22A2, respectively) are polyspecific transporters responsible for the uptake and clearance of structurally diverse cationic compounds in the liver and kidneys, respectively. Notably, it is well established that human OCT1 and OCT2 play central roles in the pharmacokinetics, pharmacodynamics, and drug-drug interactions (DDI) of many prescription medications, including metformin. Despite their importance, the basis of polyspecific cationic drug recognition and the alternating access mechanism for OCTs have remained a mystery. Here, we present four cryo-EM structures of apo, substrate-bound, and drug-bound OCT1 and OCT2 in outward-facing and outward-occluded states. Together with functional experiments, in silico docking, and molecular dynamics simulations, these structures uncover general principles of organic cation recognition by OCTs and illuminate unexpected features of the OCT alternating access mechanism. Our findings set the stage for a comprehensive structure-based understanding of OCT-mediated DDI, which will prove critical in the preclinical evaluation of emerging therapeutics.

Inflammation and Organic Cation Transporters Novel (OCTNs)

“…In good agreement, altered levels of metabolites, which are known or possibly unknown OCTN substrates, have been found in the case of chronic inflammatory diseases, such as Inflammatory Bowel Diseases (IBDs) [23]. The similarity of the AlphaFold structures of the two proteins, shown in Figure 2A, correlates well with the sequence similarity between OCTN1 and OCTN2 (Figure 2B) and also with the Cryo-EM 3D structures of OCT1, 2, and 3 sharing from 31% to 35% identity with the OCTNs [25,26]. The predicted OCTN1-2 3D structures highlight the presence of a large extracellular loop with potential N-glycosylation sites.…”