9J73

Cryo-EM structure of URAT1 in complex with benzbromarone

9J73 の概要

• エントリーDOI: 10.2210/pdb9j73/pdb
• EMDBエントリー: 61192
• 分子名称: Solute carrier family 22 member 12, [3,5-bis(bromanyl)-4-oxidanyl-phenyl]-(2-ethyl-1-benzofuran-3-yl)methanone (2 entities in total)
• 機能のキーワード: protein structure, structural protein, transport protein
• 由来する生物種: Rattus norvegicus (Norway rat)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 60675.36

構造登録者

Zhao, Y.,Yu, Z. (登録日: 2024-08-18, 公開日: 2025-08-13)

主引用文献

Yu, Z.,Hu, T.,Su, J.,Zhao, J.,Li, R.,Ma, Q.,Chen, Q.,Bai, Q.,Dong, Y.,Yuan, P.,Li, N.,Zhang, X.C.,Zhao, Y.
Molecular mechanism of drug inhibition of URAT1.
Nat Commun, 16:6551-6551, 2025

PubMed Abstract: 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.

PubMed: 40670375
DOI: 10.1038/s41467-025-61226-x

実験手法

ELECTRON MICROSCOPY (3.5 Å)