The Important Role of Transporter Structures in Drug Disposition, Efficacy, and Toxicity

The ATP-binding cassette (ABC) and solute carrier (SLC) transporters are critical determinants of drug disposition, clinical efficacy and toxicity, as they specifically mediate the influx and efflux of various substrates and drugs. ABC transporters can modulate the pharmacokinetics of many drugs via mediating the translocation of drugs across biological membranes. SLC transporters are important drug targets involved in the uptake of a broad range of compounds across the membrane. However, high-resolution experimental structures have been reported for a very limited number of transporters, which limits the study of their physiological functions. In this review, we collected structural information on ABC and SLC transporters and described the application of computational methods in structure prediction. Taking P-glycoprotein (ABCB1) and serotonin transporter (SLC6A4) as examples, we assessed the pivotal role of structure in transport mechanisms, details of ligand-receptor interactions, drug selectivity, the molecular mechanisms of drug-drug interactions (DDIs), and variability caused by genetic polymorphisms. The data collected contributes towards safer and more effective pharmacological treatments. Significance Statement The experimental structure of ABC and SLC transporters was collected, and the application of computational methods in structure prediction was described. P-glycoprotein and serotonin transporter were used as examples to reveal the pivotal role of structure in transport mechanisms, drug selectivity, the molecular mechanisms of DDIs, and differences caused by genetic polymorphisms.