Abstract
WD40 is a ubiquitous domain presented in at least 361 human proteins and acts as scaffold to form protein complexes. Among them, WDR5 protein is an important mediator in several protein complexes to exert its functions in histone modification and chromatin remodeling. Therefore, it was considered as a promising epigenetic target involving in anti-cancer drug development. In view of the protein–protein interaction nature of WDR5, we initialized a campaign to discover new peptide-mimic inhibitors of WDR5. In current study, we utilized the phage display technique and screened with a disulfide-based cyclic peptide phage library. Five rounds of biopanning were performed and isolated clones were sequenced. By analyzing the sequences, total five peptides were synthesized for binding assay. The four peptides are shown to have the moderate binding affinity. Finally, the detailed binding interactions were revealed by solving a WDR5-peptide cocrystal structure.
Highlights
Scaffold proteins, acting as mediators through protein–protein interactions, are essential components in the formation of large protein complex structures
Evidences indicated that WDR5 participates in another complex called non-specific lethal (NSL) complex [8], in which WDR5 associated with KANSL1 or KANSL2 protein and MOF (Males absent On the First, a histone H4 acetyltransferase) to acetylate the histone H4 protein [9]
According to the advantages of biopanning in solution, such as increasing the active surface between phage and the target and allowing a monovalent interaction, we used the His6-WDR5 as the target and immobilized it to Ni-NTA magnetic beads in solution
Summary
Scaffold proteins, acting as mediators through protein–protein interactions, are essential components in the formation of large protein complex structures. Evidences indicated that WDR5 participates in another complex called non-specific lethal (NSL) complex [8], in which WDR5 associated with KANSL1 or KANSL2 protein and MOF (Males absent On the First, a histone H4 acetyltransferase) to acetylate the histone H4 protein [9] Another intriguing role of WDR5 is within the nucleosome remodeling and deacetylase (NuRD) complex, a chromatinassociated protein complex that performs the dual-roles of chromatin remodeling and histone deacetylation [10]. Thomas et al [16] performed the point mutation at the Myc binding site of WDR5 (WBM site) revealed that disrupt interaction with WDR5 attenuate binding of MYC to ~80% of its chromosomal locations and disable its ability to promote induced pluripotent stem cell formation and drive tumorigenesis Based on these studies, WDR5 was considered as a novel drug target in oncology and attracted researchers worldwide to contribute the efforts. This provided a starting point for further designing potent peptide-mimic inhibitors in WDR5 drug development
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