Molecular mechanism of drug inhibition of URAT1

Zhuoya Yu, Tuo Hu, Jiawei Su, Jun Zhao, Renjie Li, Qiao Ma, Qihao Chen, Qinru Bai, Yanli Dong, Pu Yuan, Na Li (), Xuejun Cai Zhang () and Yan Zhao ()
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Zhuoya Yu: Chinese Academy of Sciences
Tuo Hu: Chinese Academy of Sciences
Jiawei Su: Chinese Academy of Sciences
Jun Zhao: Shandong Laboratory of Advanced Agricultural Sciences at Weifang
Renjie Li: Chinese Academy of Sciences
Qiao Ma: Chinese Academy of Sciences
Qihao Chen: Chinese Academy of Sciences
Qinru Bai: Chinese Academy of Sciences
Yanli Dong: Chinese Academy of Sciences
Pu Yuan: Chinese Academy of Sciences
Na Li: National Clinical Research Center for Cardiovascular Diseases
Xuejun Cai Zhang: Chinese Academy of Sciences
Yan Zhao: Chinese Academy of Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: Abstract Hyperuricemia, characterized by elevated serum urate levels, is a key factor in the pathogenesis of gout. URAT1 is essential for renal urate reabsorption and has emerged as a critical therapeutic target for managing hyperuricemia. However, the precise transport mechanism and the inhibitory effects of uricosuric drugs on URAT1 remain unclear. Here, we present structures of the double-mutant rat homolog of URAT1 in complex with its substrate urate, and the clinical drugs benzbromarone, lesinurad, verinurad, and sulfinpyrazone. The urate-bound structure elucidates key residues involved in recognizing urate, while the structures bound with drugs clearly demonstrate the distinct binding mode of each drug with URAT1. These drugs stabilize URAT1’s inward-facing state, blocking conformational transitions. Additionally, critical interactions essential for its conformational transition are identified. These findings provide a molecular framework for understanding the physiological function of URAT1 and for developing more efficacious therapies to treat hyperuricemia.

Date: 2025
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DOI: 10.1038/s41467-025-61226-x

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