OAT1 has a fundamental role in the kidney by facilitating the urinary excretion of various drugs and endogenous metabolites. Two studies now present high-resolution structures of OAT1 using cryo-EM, elucidating its intricate polyspecific transport capabilities and paving the way for structure-based drug research and development.

Organic anion transporter 1 (OAT1, also known as SLC22A6) is a critical transporter in the kidney, responsible for transporting a variety of organic anions from the blood, including metabolic byproducts, toxins, and drugs1. By facilitating the urinary excretion of these organic anions, OAT1 plays a fundamental role in maintaining kidney functions. Owing to its importance in drug transport, developing specific OAT1 inhibitors could optimize drug concentration in the bloodstream and reduce potential toxicity. For instance, during World War II, para-aminohippuric acid (PAH) was co-administered with penicillin to increase the duration of this antibiotic in the bloodstream, presumably due to PAH and penicillin competing for OAT1 in the kidney2. Today, inhibition of OAT1 via probenecid is used to limit kidney damage during treatment of retroviral infections, including HIV, using drugs such as cidofovir and tenofovir. For decades, OAT1 has been intensively studied in the context of kidney physiology, typically using PAH as a prototypical substrate2. However, the molecular mechanisms underlying its ability to recognize and transport a diverse array of substrates, a feature termed multispecificity, are still poorly understood, largely due to a lack of structural information. Now, in this issue of Nature Structural & Molecular Biology, two articles provide much-needed insights by presenting high-resolution cryo-electron microscopy (cryo-EM) structures of OAT1 in its apo state and with bound ligands3,4.