9B1M

Pyrazinoate bound human URAT1 in the inward-facing state (site1)

9B1M の概要

• エントリーDOI: 10.2210/pdb9b1m/pdb
• EMDBエントリー: 44084
• 分子名称: Solute carrier family 22 member 12, 2-acetamido-2-deoxy-beta-D-glucopyranose, PYRAZINE-2-CARBOXYLIC ACID (3 entities in total)
• 機能のキーワード: slc transporter, slc22a family, uric acid, inward facing, membrane protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 59602.71

構造登録者

Dai, Y.,Lee, C.H. (登録日: 2024-03-13, 公開日: 2024-09-18, 最終更新日: 2024-11-13)

主引用文献

Dai, Y.,Lee, C.H.
Transport mechanism and structural pharmacology of human urate transporter URAT1.
Cell Res., 34:776-787, 2024

PubMed Abstract: Urate is an endogenous product of purine metabolism in the liver. High urate levels in the blood lead to gout, a very common and painful inflammatory arthritis. Excreted urate is reabsorbed in the kidney mainly by URAT1 antiporter, a key target for anti-gout drugs. To uncover the mechanisms of urate transport and drug inhibition, we determined cryo-EM structures of human URAT1 with urate, counter anion pyrazinoate, or anti-gout drugs of different chemotypes - lesinurad, verinurad, and dotinurad. We captured the outward-to-inward transition of URAT1 during urate uptake, revealing that urate binds in a phenylalanine-rich pocket and engages with key gating residues to drive the transport cycle. In contrast to the single binding site for urate, pyrazinoate interacts with three distinct, functionally relevant sites within URAT1, a mechanism that has not yet been observed in other anion antiporters. In addition, we found that while all three drugs compete with substrates and halt the transport cycle, verinurad and dotinurad further hijack gating residues to achieve high potency. These insights advance our understanding of organic anion transport and provide a foundation for designing improved gout therapeutics.

PubMed: 39245778
DOI: 10.1038/s41422-024-01023-1

実験手法

ELECTRON MICROSCOPY (3 Å)