9eqh | pdb_00009eqh
WWP2 WW2-2,3-linker-HECT (WWP2-LH)
Structural highlights
FunctionWWP2_HUMAN E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Polyubiquitinates POU5F1 by 'Lys-63'-linked conjugation and promotes it to proteasomal degradation; in embryonic stem cells (ESCs) the ubiquitination is proposed to regulate POU5F1 protein level. Ubiquitinates EGR2 and promotes it to proteasomal degradation; in T-cells the ubiquitination inhibits activation-induced cell death. Ubiquitinates SLC11A2; the ubiquitination is enhanced by presence of NDFIP1 and NDFIP2. Ubiquitinates RPB1 and promotes it to proteasomal degradation.[1] [2] Publication Abstract from PubMedThe 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(50) of 158.3 microM (95% CI = 128.7, 195.1 microM). A structure-activity relationship by synthesis approach aided by molecular docking led to compound 11 which displayed increased potency with an IC(50) of 32.7 microM (95% CI = 24.6, 44.3 microM) for WWP1 and 269.2 microM (95% CI = 209.4, 347.9 microM) for WWP2. Molecular docking yielded active site-bound poses suggesting that the heterocyclic imidazo[4,5-b]pyrazine scaffold undertakes a pi-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. Expanding the inhibitor space of the WWP1 and WWP2 HECT E3 ligases.,Dudey AP, Rigby JM, Hughes GR, Stephenson GR, Storr TE, Chantry A, Hemmings AM J Enzyme Inhib Med Chem. 2024 Dec;39(1):2394895. doi: , 10.1080/14756366.2024.2394895. Epub 2024 Sep 2. PMID:39223706[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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