9UK4

Crystal structure of WDR5 in complex with peptide Ac-ARA-NH2

Summary for 9UK4

• Entry DOI: 10.2210/pdb9uk4/pdb
• Descriptor: WD repeat-containing protein 5, ACE-ALA-ARG-ALA-NH2 (3 entities in total)
• Functional Keywords: wd repeat, win site, mll complex, nuclear protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 34732.40

Authors

Min, J.-R.,Zhang, M.,Chen, M.-X. (deposition date: 2025-04-17, release date: 2025-10-08, Last modification date: 2025-12-10)

Primary citation

Zhang, M.,Chen, M.,Li, P.,Min, J.
Therapeutic targeting of WDR5-MLL1 by EMBOW-derived peptides suppresses leukemia progression.
Cell Chem Biol, 32:1353-, 2025

PubMed Abstract: WD40 repeat-containing protein 5 (WDR5) is a core component of the SET1/mixed lineage leukemia (MLL) complex that regulates gene expression via H3K4 methylation and plays a key role in maintaining oncogenic gene expression programs, particularly in MLL1-rearranged leukemias. In this study, we leveraged a microprotein, endogenous microprotein binder of WDR5 (EMBOW), to develop peptide-based inhibitors that specifically targeted WDR5. Through comprehensive biophysical analyses and high-resolution structural studies, we revealed that EMBOW mainly bound to the WDR5 interaction (WIN) site of WDR5. Structure-guided optimization led to the development of EMBOW-derived peptides, notably Ac7, which exhibited high affinity for WDR5 (K = 9.17 ± 4.01 nM). These peptides effectively inhibited H3K4 methylation, suppressed oncogenic gene expression, and impeded leukemia cell proliferation in vitro. Importantly, in xenograft mouse models, Ac7 demonstrated significant anti-tumor activity with low toxicity. This work offers a promising strategy for targeting epigenetic regulators with peptide-based therapeutics, providing a foundation for innovative treatments in leukemia.

PubMed: 41135522
DOI: 10.1016/j.chembiol.2025.10.002

Experimental method

X-RAY DIFFRACTION (2.12 Å)