2. Academic Validation
  3. Molecular mechanism of drug inhibition of URAT1

Molecular mechanism of drug inhibition of URAT1

  • Nat Commun. 2025 Jul 16;16(1):6551. doi: 10.1038/s41467-025-61226-x.
Zhuoya Yu # 1 2,  Tuo Hu # 1 2,  Jiawei Su # 1 2,  Jun Zhao # 3,  Renjie Li 1 2,  Qiao Ma 1 2,  Qihao Chen 1 2,  Qinru Bai 1 2,  Yanli Dong 1 2,  Pu Yuan 1 2,  Na Li 4,  Xuejun Cai Zhang 5 6,  Yan Zhao 7 8
Affiliations

Affiliations

  • 1 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  • 2 College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
  • 3 Peking University Institute of Advanced Agricultural Sciences, Shandong Laboratory of Advanced Agricultural Sciences at Weifang, Weifang, Shandong, China.
  • 4 Center for Coronary Artery Disease, Division of Cardiology, Beijing Anzhen Hospital, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Capital Medical University, National Clinical Research Center for Cardiovascular Diseases, Beijing, China. linapumc@126.com.
  • 5 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. zhangc@ibp.ac.cn.
  • 6 College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China. zhangc@ibp.ac.cn.
  • 7 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. zhaoy@ibp.ac.cn.
  • 8 College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China. zhaoy@ibp.ac.cn.
  • # Contributed equally.
PMID: 40670375 DOI: 10.1038/s41467-025-61226-x
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.

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