9DKC の概要
| エントリーDOI | 10.2210/pdb9dkc/pdb |
| EMDBエントリー | 46951 |
| 分子名称 | URAT1, 2-({1-[(4-bromonaphthalen-1-yl)methyl]-1H-imidazo[4,5-b]pyridin-2-yl}sulfanyl)-2-methylpropanoic acid (2 entities in total) |
| 機能のキーワード | membrane protein, membrane transporter, transport protein |
| 由来する生物種 | Homo sapiens |
| タンパク質・核酸の鎖数 | 1 |
| 化学式量合計 | 55836.20 |
| 構造登録者 | |
| 主引用文献 | Suo, Y.,Fedor, J.G.,Zhang, H.,Tsolova, K.,Shi, X.,Sharma, K.,Kumari, S.,Borgnia, M.,Zhan, P.,Im, W.,Lee, S.Y. Molecular basis of the urate transporter URAT1 inhibition by gout drugs. Nat Commun, 16:5178-5178, 2025 Cited by PubMed Abstract: Hyperuricemia is a condition when uric acid, a waste product of purine metabolism, accumulates in the blood. Untreated hyperuricemia can lead to crystal formation of monosodium urate in the joints, causing a painful inflammatory disease known as gout. These conditions are associated with many other diseases and affect a significant and increasing proportion of the population. The human urate transporter 1 (URAT1) is responsible for the reabsorption of ~90% of uric acid in the kidneys back into the blood, making it a primary target for treating hyperuricemia and gout. Despite decades of research and development, clinically available URAT1 inhibitors have limitations because the molecular basis of URAT1 inhibition by gout drugs remains unknown. Here we present cryo-electron microscopy structures of URAT1 alone and in complex with three clinically relevant inhibitors: benzbromarone, lesinurad, and the recently developed compound TD-3. Together with functional experiments and molecular dynamics simulations, we reveal that these inhibitors bind selectively to URAT1 in inward-open states. Furthermore, we discover differences in the inhibitor-dependent URAT1 conformations as well as interaction networks, which contribute to drug specificity. Our findings illuminate a general theme for URAT1 inhibition, paving the way for the design of next-generation URAT1 inhibitors in the treatment of gout and hyperuricemia. PubMed: 40467597DOI: 10.1038/s41467-025-60480-3 主引用文献が同じPDBエントリー |
| 実験手法 | ELECTRON MICROSCOPY (2.55 Å) |
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