5sxm | pdb_00005sxm
WDR5 in complex with MLL Win motif peptidomimetic
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 PubMedMLL1 belongs to the SET1 family of histone H3 lysine 4 (H3K4) methyltransferases, comprised of MLL1-4 and SETd1A/B. MLL1 translocations are present in acute leukemias and mutations in several family members are associated with cancer and developmental disorders. MLL1 associates with a sub-complex containing WDR5, RbBP5, ASH2L, and DPY-30 (WRAD), forming the MLL1 core complex required for H3K4 mono- and dimethylation and transcriptional activation. Core complex assembly requires interaction of WDR5 with the MLL1 WDR5 interaction (Win) motif, which is conserved across the SET1 family. Agents that mimic the SET1 family Win motif inhibit MLL1 core complex and have become an attractive approach for targeting MLL1 in cancers. Like MLL1 other SET1 family members interact with WRAD, but the roles of the Win motif in complex assembly and enzymatic activity remain unexplored. Here, we show that the Win motif is necessary for interaction of WDR5 with all members of the human SET1 family. Mutation of the Win motif-WDR5 interface severely disrupts assembly and activity of MLL1 and SETd1A complexes, but only modestly disrupts MLL2/4 and SETd1B complexes without significantly altering enzymatic activity in vitro. Notably, in the absence of WDR5, MLL3 interacts with RAD and shows enhanced activity. To further probe the role of the Win motif-WDR5 interaction, we designed a peptidomimetic that binds WDR5 (Kd~3nM) and selectively inhibits activity of MLL1 and SETd1A core complexes within the SET1 family. Our results reveal that SET1 family complexes with the weakest Win motif-WDR5 interaction are more susceptible to Win motif-based inhibitors. Targeted Disruption of the Interaction Between WD-40 Repeat Protein 5 (WDR5) and Mixed Lineage Leukemia (MLL)/SET1 Family Proteins Specifically Inhibits MLL1 and SETd1A Methyltransferase Complexes.,Alicea-Velazquez NL, Shinsky SA, Loh DM, Lee JH, Skalnik DG, Cosgrove MS J Biol Chem. 2016 Aug 25. pii: jbc.M116.752626. PMID:27563068[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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