9eqk

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

spinqualitylabelsall models 9eqk, resolution 3.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9eqk is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function WWP1_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. Ubiquitinates ERBB4 isoforms JM-A CYT-1 and JM-B CYT-1, KLF2, KLF5 and TP63 and promotes their proteasomal degradation. Ubiquitinates RNF11 without targeting it for degradation. Ubiquitinates and promotes degradation of TGFBR1; the ubiquitination is enhanced by SMAD7. Ubiquitinates SMAD6 and SMAD7. Ubiquitinates and promotes degradation of SMAD2 in response to TGF-beta signaling, which requires interaction with TGIF. Publication Abstract from PubMed 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(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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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