Impact of WIN site inhibitor on the WDR5 interactome.
The chromatin-associated protein WDR5 is a promising pharmacological target in cancer, with most drug discovery efforts directed against an arginine-binding cavity in WDR5 called the WIN site. Despite a clear expectation that WIN site inhibitors will alter the repertoire of WDR5 interaction partners, their impact on the WDR5 interactome remains ... unknown. Here, we use quantitative proteomics to delineate how the WDR5 interactome is changed by WIN site inhibition. We show that the WIN site inhibitor alters the interaction of WDR5 with dozens of proteins, including those linked to phosphatidylinositol 3-kinase (PI3K) signaling. As proof of concept, we demonstrate that the master kinase PDPK1 is a bona fide high-affinity WIN site binding protein that engages WDR5 to modulate transcription of genes expressed in the G2 phase of the cell cycle. This dataset expands our understanding of WDR5 and serves as a resource for deciphering the action of WIN site inhibitors.
Mesh Terms:
3-Phosphoinositide-Dependent Protein Kinases, Amino Acid Sequence, Binding Sites, Drug Discovery, G2 Phase, Gene Expression Regulation, HEK293 Cells, Humans, Immunoprecipitation, Intracellular Signaling Peptides and Proteins, Models, Molecular, Molecular Targeted Therapy, Protein Binding
3-Phosphoinositide-Dependent Protein Kinases, Amino Acid Sequence, Binding Sites, Drug Discovery, G2 Phase, Gene Expression Regulation, HEK293 Cells, Humans, Immunoprecipitation, Intracellular Signaling Peptides and Proteins, Models, Molecular, Molecular Targeted Therapy, Protein Binding
Cell Rep
Date: Dec. 19, 2020
PubMed ID: 33472061
View in: Pubmed Google Scholar
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