6pg4 | pdb_00006pg4
WDR5delta32 bound to (2-methyl-1H-imidazol-4-yl)methanol
Structural highlights
Function[WDR5_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 PubMedThe WD40-repeat protein WDR5 scaffolds various epigenetic writers and is a critical component of the mammalian SET/MLL histone methyltransferase complex. Dysregulation of the MLL1 catalytic function is associated with mixed-lineage leukemia, and antagonism of the WDR5-MLL1 interaction by small molecules has been proposed as a therapeutic strategy for MLL-rearranged cancers. Small molecule binders of the "WIN" site of WDR5 that cause displacement from chromatin have been additionally implicated to be of broader use in cancer treatment. In this study, a fragment screen with Surface Plasmon Resonance (SPR) was used to identify a highly ligand-efficient imidazole-containing compound that is bound in the WIN site. The subsequent medicinal chemistry campaign-guided by a suite of high-resolution cocrystal structures with WDR5-progressed the initial hit to a low micromolar binder. One outcome from this study is a moiety that substitutes well for the side chain of arginine; a tripeptide containing one such substitution was resolved in a high resolution structure (1.5 A) with a binding mode analogous to the native tripeptide. SPR furthermore indicates a similar residence time (k d = approximately 0.06 s(-1)) for these two analogs. This novel scaffold therefore represents a possible means to overcome the potential permeability issues of WDR5 ligands that possess highly basic groups like guanidine. The series reported here furthers the understanding of the WDR5 WIN site and functions as a starting point for the development of more potent WDR5 inhibitors that may serve as cancer therapeutics. Fragment screening for a protein-protein interaction inhibitor to WDR5.,Dennis ML, Morrow BJ, Dolezal O, Cuzzupe AN, Stupple AE, Newman J, Bentley J, Hattarki M, Nuttall SD, Foitzik RC, Street IP, Stupple PA, Monahan BJ, Peat TS Struct Dyn. 2019 Nov 14;6(6):064701. doi: 10.1063/1.5122849. eCollection 2019, Nov. PMID:31768400[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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