ArticleThe Journal of biological chemistry2016
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.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 69 citations in OpenAlex.
- Promiscuous RNA binding by WDR5 remodels the KMT2A (MLL1) histone methyltransferase complex to an inactive state.Molecular cell · 2026Article
- Promiscuous RNA binding by WDR5 remodels the KMT2A (MLL1) histone methyltransferase complex to an inactive state.bioRxiv : the preprint server for biology · 2026Article
- ChemScreener: an active learning enabled hit discovery workflow with WDR5 inhibitor case study.Journal of cheminformatics · 2026Article
- Probing the Cancer Mutational Landscape of KMT2 Regulatory Subunits.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- A Site-Specific Self-Association of a Protein Hub Drives Its Phase Separation.ACS chemical biology · 2026Article
- A novel mutation inFrontiers in neuroscience · 2026Article
- Insights into WDR5: unveiling its functions, regulation, and impact on skeletal muscle.Epigenetics · 2025Review
- Therapeutic Targeting of Protein Lysine and Arginine Methyltransferases: Principles and Strategies for Inhibitor Design.International journal of molecular sciences · 2025Review
- Molecular determinants for recognition of serotonylated chromatin.Nucleic acids research · 2025Article
- Lysine and arginine methylation of transcription factors.Cellular and molecular life sciences : CMLS · 2024Review
- Article
- Overlapping characteristics of weak interactions of two transcriptional regulators with WDR5.International journal of biological macromolecules · 2024Article
- Ribosome subunit attrition and activation of the p53-MDM4 axis dominate the response of MLL-rearranged cancer cells to WDR5 WIN site inhibition.bioRxiv : the preprint server for biology · 2024Article
- WD Repeat Domain 5 Inhibitors for Cancer Therapy: Not What You Think.Journal of clinical medicine · 2024Review
- Structure-Based Discovery of Potent, Orally Bioavailable Benzoxazepinone-Based WD Repeat Domain 5 Inhibitors.Journal of medicinal chemistry · 2023Article
- Discovery of Potent and Selective WDR5 Proteolysis Targeting Chimeras as Potential Therapeutics for Pancreatic Cancer.Journal of medicinal chemistry · 2023Article
- Article
- WDR5 represents a therapeutically exploitable target for cancer stem cells in glioblastoma.Genes & development · 2023Article
- Hierarchical assembly of the MLL1 core complex regulates H3K4 methylation and is dependent on temperature and component concentration.The Journal of biological chemistry · 2023Article
- Structure-based discovery of potent WD repeat domain 5 inhibitors that demonstrate efficacy and safety in preclinical animal models.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
MLL1 belongs to the SET1 family of histone H3 lysine 4 (H3K4) methyltransferases, composed 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 subcomplex 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 Win (WDR5 interaction) motif, which is conserved across the SET1 family. Agents that mimic the SET1 family Win motif inhibit the 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 (K
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