9L63

A novel allosteric covalent inhibitory site of fucosyltransferase 8 revealed by crystal structures

これはPDB形式変換不可エントリーです。

9L63 の概要

• エントリーDOI: 10.2210/pdb9l63/pdb
• 分子名称: Alpha-(1,6)-fucosyltransferase, 1-[(~{Z})-octadec-9-enoyl]oxy-2,5-bis(oxidanylidene)pyrrolidine-3-sulfonic acid (3 entities in total)
• 機能のキーワード: inhibitors, complex, allosteric, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 115737.19

構造登録者

Jiang, J.,Fang, P. (登録日: 2024-12-24, 公開日: 2026-01-07, 最終更新日: 2026-04-01)

主引用文献

Jiang, J.,He, D.,Ke, M.,Qin, J.,Yang, G.,Yu, B.,Wang, J.,Fang, P.
Exploiting human fucosyltransferase 8 allostery with a covalent inhibitor for core fucosylation suppression.
Nat Commun, 17:-, 2026

PubMed Abstract: Core fucosylation, catalyzed by fucosyltransferase 8 (FUT8), plays critical roles in cancer progression, immune evasion, and drug resistance, making it a compelling therapeutic target. However, development of selective FUT8 inhibitors has been hindered by shared substrate specificity of fucosyltransferases. Here, we report the discovery of a previously unrecognized allosteric site on FUT8 and the development of a low-toxicity covalent inhibitor, CAIF (stearic acid-N-hydroxysuccinimide ester-dimethylimidazolium bromide), through structure-based drug design. High-throughput screening and crystallographic studies reveal that small molecules such as NH125 bind to a channel-like allosteric pocket, inducing conformational changes that disrupt FUT8 activity. Leveraging these insights, we design CAIF to covalently target lysine K216 within the allosteric site. CAIF exhibits minimal cytotoxicity and significantly inhibits core fucosylation and cancer cell invasion in cellular assays. This work establishes CAIF as a lead compound for further optimization and development, offering a framework for targeting glycosyltransferases through allosteric and covalent inhibition strategies.

PubMed: 41667477
DOI: 10.1038/s41467-026-68971-7

実験手法

X-RAY DIFFRACTION (2.66 Å)