9EQK

WWP1 WW2-2,3-linker-WW3-WW4-HECT (WWP1-2L34H) with ordered WW2 domain

Summary for 9EQK

• Entry DOI: 10.2210/pdb9eqk/pdb
• Descriptor: NEDD4-like E3 ubiquitin-protein ligase WWP1 (2 entities in total)
• Functional Keywords: ubiquitin, ligase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 130144.83

Authors

Dudey, A.P.,Hemmings, A.M. (deposition date: 2024-03-21, release date: 2024-05-15, Last modification date: 2024-09-18)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (3 Å)