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8RD1

HUWE1 WWE domain in complex with compound 4

Summary for 8RD1
Entry DOI10.2210/pdb8rd1/pdb
DescriptorE3 ubiquitin-protein ligase HUWE1, CHLORIDE ION, 2-(2-hydroxy-2-oxoethyl)-1,3-bis(oxidanylidene)isoindole-5-carboxylic acid, ... (4 entities in total)
Functional Keywordswwe domain, ligase
Biological sourceHomo sapiens (human)
Total number of polymer chains4
Total formula weight43003.04
Authors
Muenzker, L.,Zak, K.M.,Boettcher, J. (deposition date: 2023-12-07, release date: 2024-07-31, Last modification date: 2024-08-07)
Primary citationMunzker, L.,Kimani, S.W.,Fowkes, M.M.,Dong, A.,Zheng, H.,Li, Y.,Dasovich, M.,Zak, K.M.,Leung, A.K.L.,Elkins, J.M.,Kessler, D.,Arrowsmith, C.H.,Halabelian, L.,Bottcher, J.
A ligand discovery toolbox for the WWE domain family of human E3 ligases.
Commun Biol, 7:901-901, 2024
Cited by
PubMed Abstract: The WWE domain is a relatively under-researched domain found in twelve human proteins and characterized by a conserved tryptophan-tryptophan-glutamate (WWE) sequence motif. Six of these WWE domain-containing proteins also contain domains with E3 ubiquitin ligase activity. The general recognition of poly-ADP-ribosylated substrates by WWE domains suggests a potential avenue for development of Proteolysis-Targeting Chimeras (PROTACs). Here, we present novel crystal structures of the HUWE1, TRIP12, and DTX1 WWE domains in complex with PAR building blocks and their analogs, thus enabling a comprehensive analysis of the PAR binding site structural diversity. Furthermore, we introduce a versatile toolbox of biophysical and biochemical assays for the discovery and characterization of novel WWE domain binders, including fluorescence polarization-based PAR binding and displacement assays, N-NMR-based binding affinity assays and F-NMR-based competition assays. Through these assays, we have characterized the binding of monomeric iso-ADP-ribose (iso-ADPr) and its nucleotide analogs with the aforementioned WWE proteins. Finally, we have utilized the assay toolbox to screen a small molecule fragment library leading to the successful discovery of novel ligands targeting the HUWE1 WWE domain.
PubMed: 39048679
DOI: 10.1038/s42003-024-06584-w
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.896 Å)
Structure validation

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PDB entries from 2024-11-06

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