Urate anion exchanger 1 (URAT1)

Urate anion exchanger 1 (URAT1) is the primary renal transporter responsible for reabsorbing approximately 90% of filtered uric acid back into the bloodstream, making it a critical regulator of blood uric acid levels[4]. Located on the apical membrane of proximal tubular cells in the kidney, URAT1 functions as an electroneutral antiporter that exchanges urate for monovalent organic or inorganic anions[7][9]. The transporter belongs to the major facilitator superfamily and adopts a characteristic 12-transmembrane domain structure with an inward-open binding conformation that accommodates large inhibitor molecules[4]. URAT1 is a major therapeutic target for treating hyperuricemia and gout, conditions characterized by elevated blood uric acid levels[3][4]. Multiple urate-lowering drugs, including lesinurad, verinurad, and benzbromarone, work by inhibiting URAT1 and reducing uric acid reabsorption, thereby increasing urinary urate excretion[4]. Recent structural studies using cryo-electron microscopy have revealed that these inhibitors bind to URAT1's central cavity and stabilize the inward-open conformation, providing insights into inhibitor specificity and binding mechanisms[4].

Other names

Human urate transporter 1 (hURAT1)Solute carrier family 22 member 12SLC22A12 (gene name)

Inhibition by competitive binding: Clinical inhibitors bind to the central cavity of URAT1 in the inward-open conformation, stabilizing this state and preventing urate transport. Conformational locking: Inhibitors lock the transporter in the inward-open conformation, preventing the conformational changes required for urate reabsorption. Aromatic clamp interaction: Inhibitors like lesinurad and TD-3 interact with aromatic residues (particularly F241 and F449) that form an "aromatic clamp" in the binding cavity. Hydrophobic region engagement: Larger inhibitors occupy the hydrophobic region of the central cavity through interactions with residues like M214.