4ia9
Crystal structure of human WD REPEAT DOMAIN 5 in complex with 2-chloro-4-fluoro-3-methyl-N-[2-(4-methylpiperazin-1-yl)-5-nitrophenyl]benzamide
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 PubMedThe WD40-repeat protein WDR5 plays a critical role in maintaining the integrity of MLL complexes and fully activating their methyltransferase function. MLL complexes, the trithorax-like family of SET1 methyltransferases, catalyze trimethylation of lysine 4 on histone 3, and they have been widely implicated in various cancers. Antagonism of WDR5 and MLL subunit interaction by small molecules has recently been presented as a practical way to inhibit activity of the MLL1 complex, and N-(2-(4-methylpiperazin-1-yl)-5-substituted-phenyl) benzamides were reported as potent and selective antagonists of such an interaction. Here, we describe the protein crystal structure guided optimization of prototypic compound 2 (K dis = 7 muM), leading to identification of more potent antagonist 47 (K dis = 0.3 muM). Synthesis, Optimization, and Evaluation of Novel Small Molecules as Antagonists of WDR5-MLL Interaction.,Bolshan Y, Getlik M, Kuznetsova E, Wasney GA, Hajian T, Poda G, Nguyen KT, Wu H, Dombrovski L, Dong A, Senisterra G, Schapira M, Arrowsmith CH, Brown PJ, Al-Awar R, Vedadi M, Smil D ACS Med Chem Lett. 2013 Feb 4;4(3):353-7. doi: 10.1021/ml300467n. eCollection, 2013 Mar 14. PMID:24900672[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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