9EQH

WWP2 WW2-2,3-linker-HECT (WWP2-LH)

9EQH の概要

• エントリーDOI: 10.2210/pdb9eqh/pdb
• 分子名称: Isoform 2 of NEDD4-like E3 ubiquitin-protein ligase WWP2, GLYCEROL, SODIUM ION, ... (4 entities in total)
• 機能のキーワード: ubiquitin, ligase
• 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: 53648.72

構造登録者

Dudey, A.P.,Hemmings, A.M. (登録日: 2024-03-21, 公開日: 2024-05-15, 最終更新日: 2024-09-18)

主引用文献

Dudey, A.P.,Rigby, J.M.,Hughes, G.R.,Stephenson, G.R.,Storr, T.E.,Chantry, A.,Hemmings, A.M.
Expanding the inhibitor space of the WWP1 and WWP2 HECT E3 ligases.
J Enzyme Inhib Med Chem, 39:2394895-2394895, 2024

PubMed Abstract: The HECT E3 ubiquitin ligases 1 (WWP1) and 2 (WWP2) are responsible for the ubiquitin-mediated degradation of key tumour suppressor proteins and are dysregulated in various cancers and diseases. Here we expand their limited inhibitor space by identification of NSC-217913 displaying a WWP1 IC of 158.3 µM (95% CI = 128.7, 195.1 µM). A structure-activity relationship by synthesis approach aided by molecular docking led to compound which displayed increased potency with an IC of 32.7 µM (95% CI = 24.6, 44.3 µM) for WWP1 and 269.2 µM (95% CI = 209.4, 347.9 µM) for WWP2. Molecular docking yielded active site-bound poses suggesting that the heterocyclic imidazo[4,5-]pyrazine scaffold undertakes a π-stacking interaction with the phenolic group of tyrosine, and the ethyl ester enables strong ion-dipole interactions. Given the therapeutic potential of WWP1 and WWP2, we propose that compound 11 may provide a basis for future lead compound development.

PubMed: 39223706
DOI: 10.1080/14756366.2024.2394895

実験手法

X-RAY DIFFRACTION (2.05 Å)