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| Title | Molecular mechanisms of urate transport by the native human URAT1 and its inhibition by anti-gout drugs. |
|---|---|
| Journal, issue, pages | Cell Discov, Vol. 11, Issue 1, Page 33, Year 2025 |
| Publish date | Apr 1, 2025 |
Authors | Canrong Wu / Chao Zhang / Sanshan Jin / James Jiqi Wang / Antao Dai / Jiuyin Xu / Heng Zhang / Xuemei Yang / Xinheng He / Qingning Yuan / Wen Hu / Youwei Xu / Mingwei Wang / Yi Jiang / Dehua Yang / H Eric Xu / ![]() |
| PubMed Abstract | 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 ...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. |
External links | Cell Discov / PubMed:40169562 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.23 - 3.6 Å |
| Structure data | EMDB-61399, PDB-9jdv: EMDB-61401, PDB-9jdy: EMDB-61402, PDB-9jdz: EMDB-61403, PDB-9je0: EMDB-61404, PDB-9je1: |
| Chemicals | ![]() ChemComp-URC: ![]() ChemComp-HOH: ![]() PDB-1aij: ![]() PDB-1ail: ![]() ChemComp-R75: ![]() PDB-1aik: |
| Source |
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Keywords | TRANSPORT PROTEIN / URAT1 |
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homo sapiens (human)
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