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Molecular mechanisms of urate transport by the native human URAT1 and its inhibition by anti-gout drugs

Cell Discov. 2025-04; 
Canrong Wu, Chao Zhang, Sanshan Jin, James Jiqi Wang, Antao Dai, Jiuyin Xu, Heng Zhang, Xuemei Yang, Xinheng He, Qingning Yuan, Wen Hu, Youwei Xu, Mingwei Wang, Yi Jiang, Dehua Yang, H Eric Xu
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Catalog Peptides After centrifugation, the supernatant was incubated with anti-DYKDDDDK G1 Affinity Resin (GenScript) for 3 h at 4 °C. The complex sample was eluted in a buffer containing 20 mM HEPES (pH 7.4), 150 mM NaCl, 0.01% (w/v) LMNG, 0.002% CHS, 10 μM ligand, and 0.2 mg/mL Flag peptide (GenScript). Get A Quote

摘要

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 mutagene... More

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