Molecular 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 reabsorption and hURAT1 inhibition. Our findings elucidate the molecular basis of urate transport and anti-gout medication action and provide a structural framework for the rational design of next-generation therapies for hyperuricemia and gout.
Authors
- Wen Hu (ORCID: https://orcid.org/0009-0003-8361-6432)
- Youwei Xu (ORCID: https://orcid.org/0000-0001-8069-7511)
- Xinheng He (ORCID: https://orcid.org/0000-0001-7813-5480)
- Canrong Wu (ORCID: https://orcid.org/0000-0002-2272-3838)
- H. Eric Xu (ORCID: https://orcid.org/0000-0002-6829-8144)
- James Jiqi Wang (ORCID: https://orcid.org/0000-0002-8878-668X)
- Xuemei Yang (ORCID: https://orcid.org/0000-0003-4005-978X)
- Yi Jiang (ORCID: https://orcid.org/0000-0002-0723-1413)
- Dehua Yang (ORCID: https://orcid.org/0000-0003-3028-3243)
- Antao Dai (ORCID: https://orcid.org/0000-0003-4241-5346)
- Heng Zhang (ORCID: https://orcid.org/0000-0002-9441-8277)
- Ming‐Wei Wang (ORCID: https://orcid.org/0000-0001-6550-9017)
- Sanshan Jin (ORCID: https://orcid.org/0000-0002-2523-1767)
- Qingning Yuan (ORCID: https://orcid.org/0009-0007-2979-5168)
- Jiuyin Xu (ORCID: https://orcid.org/0009-0001-9411-955X)
- Yong Zhang (ORCID: https://orcid.org/0000-0002-7400-5803)
Institutions
- Shanghai Jiao Tong University (CN)
- Chinese Academy of Sciences (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Fudan University (CN)
- Peking Union Medical College Hospital (CN)
- Ruijin Hospital (CN)
- Shanghai Institute of Materia Medica (CN)
- National Center for Drug Screening (CN)
- Institute of Deep-Sea Science and Engineering (CN)
- Tongji Hospital (CN)
- University of Chinese Academy of Sciences (CN)
- Huazhong University of Science and Technology (CN)
- The University of Tokyo (JP)
- Hainan Medical University (CN)
Publication Details
- Journal
- Cell Discovery
- Published
- 2025-04-01
- DOI
- https://doi.org/10.1038/s41421-025-00779-z
- Citations
- 10
- Primary Topic
- Gout, Hyperuricemia, Uric Acid
- Type
- article
- Field-Weighted Citation Impact
- 14.31
Funders
- National Natural Science Foundation of China