Molecular mechanisms of urate transport by the native human URAT1 and its inhibition by anti-gout drugs
文献类型：期刊论文
| 作者 | Wu, Canrong14,15; Zhang, Chao12,13; Jin, Sanshan10,11; Wang, James Jiqi8,9; Dai, Antao7,12; Xu, Jiuyin11,14; Zhang, Heng14; Yang, Xuemei15; He, Xinheng14; Yuan, Qingning14 |
| 刊名 | CELL DISCOVERY
 |
| 出版日期 | 2025-04-01 |
| 卷号 | 11期号:1页码:12 |
| DOI | 10.1038/s41421-025-00779-z |
| 英文摘要 | 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 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. |
| WOS关键词 | ORGANIC ANION TRANSPORTERS ; IDENTIFICATION ; LESINURAD |
| 资助项目 | National Natural Science Foundation of China (National Science Foundation of China) ; Chinese Academy of Sciences[2022YFC2703105] ; National Key R&D Program of China[32301016] ; National Key R&D Program of China[32130022] ; National Key R&D Program of China[32171187] ; National Key R&D Program of China[82121005] ; National Key R&D Program of China[82273985] ; National Natural Science Foundation of China[XDB37030103] ; CAS Strategic Priority Research Program ; Shanghai Municipal Science and Technology Major Project[2023YFA1800804] ; National Key Basic Research Program of China[21JC1401600] ; Shanghai Municipality Science and Technology Development Fund[23XD1400900] ; Program of Shanghai Academic/Technology Research Leader[ZDKJ2021028] ; Hainan Provincial Major Science and Technology Project |
| WOS研究方向 | Cell Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:001457032600001 |
| 出版者 | SPRINGERNATURE |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/316923]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Wu, Canrong; Jiang, Yi; Yang, Dehua; Xu, H. Eric |
| 作者单位 | 1.Peking Union Med Coll Hosp, Inst Clin Med, Ctr Drug Res & Evaluat, Natl Infrastruct Translat Med, Beijing, Peoples R China 2.Univ Chinese Acad Sci, Beijing, Peoples R China 3.Hainan Med Univ, Sch Pharm, Haikou, Hainan, Peoples R China 4.Univ Tokyo, Sch Sci, Dept Chem, Tokyo, Japan 5.Fudan Univ, Sch Basic Med Sci, Dept Pharmacol, Shanghai, Peoples R China 6.Res Ctr Deepsea Bioresources, Sanya, Hainan, Peoples R China 7.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai, Peoples R China 8.Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Hubei Key Lab Genet & Mol Mech Cardiol Disorders, Wuhan, Hubei, Peoples R China 9.Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Internal Med,Div Cardiol, Wuhan, Hubei, Peoples R China 10.Lingang Lab, Shanghai, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wu, Canrong,Zhang, Chao,Jin, Sanshan,et al. Molecular mechanisms of urate transport by the native human URAT1 and its inhibition by anti-gout drugs[J]. CELL DISCOVERY,2025,11(1):12. |
| APA | Wu, Canrong.,Zhang, Chao.,Jin, Sanshan.,Wang, James Jiqi.,Dai, Antao.,...&Xu, H. Eric.(2025).Molecular mechanisms of urate transport by the native human URAT1 and its inhibition by anti-gout drugs.CELL DISCOVERY,11(1),12. |
| MLA | Wu, Canrong,et al."Molecular mechanisms of urate transport by the native human URAT1 and its inhibition by anti-gout drugs".CELL DISCOVERY 11.1(2025):12. |
入库方式： OAI收割
来源：上海药物研究所
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