7PR8

Crystal structure of human heparanase in complex with covalent inhibitor GR109

7PR8 の概要

• エントリーDOI: 10.2210/pdb7pr8/pdb
• 関連するPDBエントリー: 7PR7
• 分子名称: Heparanase 50 kDa subunit, Heparanase 8 kDa subunit, alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total)
• 機能のキーワード: glycoside hydrolase, carbohydrate, glucuronidase, gh79, heparan sulfate
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 53538.67

構造登録者

Wu, L.,Armstrong, Z.,Davies, G.J. (登録日: 2021-09-21, 公開日: 2022-08-03, 最終更新日: 2024-10-09)

主引用文献

de Boer, C.,Armstrong, Z.,Lit, V.A.J.,Barash, U.,Ruijgrok, G.,Boyango, I.,Weitzenberg, M.M.,Schroder, S.P.,Sarris, A.J.C.,Meeuwenoord, N.J.,Bule, P.,Kayal, Y.,Ilan, N.,Codee, J.D.C.,Vlodavsky, I.,Overkleeft, H.S.,Davies, G.J.,Wu, L.
Mechanism-based heparanase inhibitors reduce cancer metastasis in vivo.
Proc.Natl.Acad.Sci.USA, 119:e2203167119-e2203167119, 2022

PubMed Abstract: Heparan sulfate proteoglycans (HSPGs) mediate essential interactions throughout the extracellular matrix (ECM), providing signals that regulate cellular growth and development. Altered HSPG composition during tumorigenesis strongly aids cancer progression. Heparanase (HPSE) is the principal enzyme responsible for extracellular heparan sulfate catabolism and is markedly up-regulated in aggressive cancers. HPSE overactivity degrades HSPGs within the ECM, facilitating metastatic dissemination and releasing mitogens that drive cellular proliferation. Reducing extracellular HPSE activity reduces cancer growth, but few effective inhibitors are known, and none are clinically approved. Inspired by the natural glycosidase inhibitor cyclophellitol, we developed nanomolar mechanism-based, irreversible HPSE inhibitors that are effective within physiological environments. Application of cyclophellitol-derived HPSE inhibitors reduces cancer aggression in cellulo and significantly ameliorates murine metastasis. Mechanism-based irreversible HPSE inhibition is an unexplored anticancer strategy. We demonstrate the feasibility of such compounds to control pathological HPSE-driven malignancies.

PubMed: 35881786
DOI: 10.1073/pnas.2203167119

実験手法

X-RAY DIFFRACTION (1.66 Å)