biostudies-literatureWu CNational Natural Science Foundation of China (National Science Foundation of China)33https://www.ebi.ac.uk/biostudies/studies/S-EPMC11962085biostudies-literatureUnknown11(1)Gout, a common and painful disease, stems from hyperuricemia, where elevated blood urate levels lead to urate crystal formation in joints and kidneys. The human urate transporter 1 (hURAT1) plays a critical role in urate homeostasis by facilitating urate reabsorption in the renal proximal tubule, making it a key target for gout therapy. Pharmacological inhibition of hURAT1 with drugs such as dotinurad, benzbromarone, lesinurad, and verinurad promotes urate excretion and alleviates gout symptoms. Here, we present cryo-electron microscopy structures of native hURAT1 bound with these anti-gout drugs in the inward-open state, and with urate in inward-open, outward-open, and occluded states. Complemented by mutagenesis and cell-based assays, these structures reveal the mechanisms of urate reabsCell discoveryMolecular mechanisms of urate transport by the native human URAT1 and its inhibition by anti-gout drugs.PMC119620853210022Jin SDai AHu WZhang HYuan QWu CYang DXu HEXu JYang XWang MJiang YHe XZhang CWang JJXu YfalseMolecular mechanisms of urate transport by the native human URAT1 and its inhibition by anti-gout drugs.Gout, a common and painful disease, stems from hyperuricemia, where elevated blood urate levels lead to urate crystal formation in joints and kidneys. The human urate transporter 1 (hURAT1) plays a critical role in urate homeostasis by facilitating urate reabsorption in the renal proximal tubule, making it a key target for gout therapy. Pharmacological inhibition of hURAT1 with drugs such as dotinurad, benzbromarone, lesinurad, and verinurad promotes urate excretion and alleviates gout symptoms. Here, we present cryo-electron microscopy structures of native hURAT1 bound with these anti-gout drugs in the inward-open state, and with urate in inward-open, outward-open, and occluded states. Complemented by mutagenesis and cell-based assays, these structures reveal the mechanisms of urate reabs2025-01-01T00:00:00Z2025 Apr2026-06-01T14:34:04.637Z2026-04-08T13:25:27.471ZS-EPMC119620854016956210.1038/s41421-025-00779-z