Molecular mechanism of drug inhibition of URAT1
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.
Authors
- Zhuoya Yu (ORCID: https://orcid.org/0000-0002-0370-2871)
- Peng Yuan (ORCID: https://orcid.org/0000-0002-5968-0368)
- Yanli Dong (ORCID: https://orcid.org/0000-0002-7919-3276)
- Tuo Hu (ORCID: https://orcid.org/0000-0001-7069-1466)
- Xuejun C. Zhang (ORCID: https://orcid.org/0000-0001-6726-3698)
- Yan Zhao (ORCID: https://orcid.org/0000-0002-4348-256X)
- Jiawei Su (ORCID: https://orcid.org/0000-0002-6124-5007)
- Qiao Ma (ORCID: https://orcid.org/0000-0003-0614-2192)
- Qihao Chen
- Jun Zhao (ORCID: https://orcid.org/0009-0006-6190-0469)
- Renjie Li (ORCID: https://orcid.org/0000-0002-5646-1493)
- Na Li
- Qinru Bai (ORCID: https://orcid.org/0009-0008-2667-4405)
Institutions
- Chinese Academy of Sciences (CN)
- Institute of Biophysics (CN)
- Beijing Anzhen Hospital (CN)
- University of Chinese Academy of Sciences (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-07-16
- DOI
- https://doi.org/10.1038/s41467-025-61226-x
- Citations
- 5
- Primary Topic
- Gout, Hyperuricemia, Uric Acid
- Type
- article
- Field-Weighted Citation Impact
- 7.15
Funders
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- National Key Research and Development Program of China
- Institute of Biophysics, Chinese Academy of Sciences