24XP

Crystal structure of WDR5 F133A variant in complex with MBD3C

Summary for 24XP

• Entry DOI: 10.2210/pdb24xp/pdb
• Descriptor: WD repeat-containing protein 5, Methyl-CpG-binding domain protein 3c (3 entities in total)
• Functional Keywords: wdr5, mbd3c, win motif, nuclear protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 71793.48

Authors

Yang, Y.,Liu, Y. (deposition date: 2026-03-23, release date: 2026-05-06, Last modification date: 2026-05-13)

Primary citation

Pan, Y.,Li, H.,Peng, S.,Wang, H.,Wu, Z.,Hang, T.,Liu, Y.,Yang, Y.
Water-mediated compensation preserves WIN motif binding in WDR5 aromatic mutants.
Biochem.Biophys.Res.Commun., 819:153842-153842, 2026

PubMed Abstract: WD repeat-containing protein 5 (WDR5) recognizes canonical arginine-containing WDR5-interacting (WIN) motifs through a highly conserved binding pocket, in which WDR5 Phe133 and Phe263 are thought to stabilize the central arginine via cation-π interactions. Here, we re-evaluate the contribution of these residues using the MBD3C WIN peptide, which exhibits dual-site engagement with the WIN and B pockets. Isothermal titration calorimetry reveals that WDR5 F133A and F263A variants retain robust binding affinity to MBD3C, with only an approximately twofold reduction in affinity for F133A and a modest increase for F263A compared to wild-type WDR5. Crystal structures of both variant complexes at 1.30 Å and 1.57 Å resolution reveal that the peptide adopts a canonical binding mode despite disruption of the aromatic cage. The cavities created by phenylalanine-to-alanine substitutions are occupied by newly recruited, well-ordered water molecules that integrate into the conserved hydration network and form compensatory hydrogen-bonding interactions with the arginine side chain. These results indicate that Phe133 and Phe263 are not strictly required for WIN motif recognition in this context and demonstrate that solvent-mediated interactions can stabilize ligand binding in the absence of canonical cation-π contacts. Together, these findings highlight the adaptability of the WDR5 WIN binding pocket and provide a refined framework for understanding ligand recognition.

PubMed: 42048953
DOI: 10.1016/j.bbrc.2026.153842

Experimental method

X-RAY DIFFRACTION (1.3 Å)