8f1g
From Proteopedia
Crystal structure of human WDR5 in complex with compound WM662
Structural highlights
FunctionWDR5_HUMAN Contributes to histone modification. May position the N-terminus of histone H3 for efficient trimethylation at 'Lys-4'. As part of the MLL1/MLL complex it is involved in methylation and dimethylation at 'Lys-4' of histone H3. H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation. As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues. May regulate osteoblasts differentiation.[1] [2] [3] [4] [5] Publication Abstract from PubMedWD repeat domain 5 (WDR5) is a member of the WD40-repeat protein family that plays a critical role in multiple processes. It is also a prominent target for pharmacological inhibition in diseases such as cancer, aging, and neurodegenerative disorders. Interactions between WDR5 and various partners are essential for sustaining its function. Most drug discovery efforts center on the WIN (WDR5 interaction motif) site of WDR5 that is responsible for the recruitment of WDR5 to chromatin. Here, we describe the discovery of novel WDR5 inhibitors for the other WBM (WDR5 binding motif) pocket on this scaffold protein, to disrupt WDR5 interaction with its binding partner MYC by high-throughput biochemical screening, subsequent molecule optimization, and biological assessment. These new WDR5 inhibitors provide useful probes for future investigations of WDR5 and an avenue for targeting WDR5 as a therapeutic strategy. Discovery of Potent Small-Molecule Inhibitors of WDR5-MYC Interaction.,Ding J, Li G, Liu H, Liu L, Lin Y, Gao J, Zhou G, Shen L, Zhao M, Yu Y, Guo W, Hommel U, Ottl J, Blank J, Aubin N, Wei Y, He H, Sage DR, Atadja PW, Li E, Jain RK, Tallarico JA, Canham SM, Chiang YL, Wang H ACS Chem Biol. 2023 Jan 3. doi: 10.1021/acschembio.2c00843. PMID:36594833[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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