9KD5

Structure of WDR5 in complex with WIN motif containing Kif2A S121G

Summary for 9KD5

• Entry DOI: 10.2210/pdb9kd5/pdb
• Descriptor: WD repeat-containing protein 5, Kinesin-like protein KIF2A (3 entities in total)
• Functional Keywords: wdr5, kif2a, win motif, chromatin, nuclear protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 71094.58

Authors

Xu, L.,Yang, Y. (deposition date: 2024-11-03, release date: 2025-05-21)

Primary citation

Yang, Y.,Zhang, S.,Wu, Z.,Li, W.,Sun, X.,Xuan, Y.,Hang, T.,Xu, L.,Chen, X.
Crystal structures of Kif2A complexed with WDR5 reveal the structural plasticity of WIN-S7 sites.
Acta Biochim.Biophys.Sin., 2025

PubMed Abstract: Chromosome congression and spindle assembly are essential for genomic stability and proper cell division, with deficiencies in these processes linked to tumorigenesis. WD repeat-containing protein 5 (WDR5), a core component of the mixed lineage leukemia (MLL) methyltransferase complex, directly binds to kinesin family member 2A (Kif2A) to regulate these mitotic events. Despite the importance of this interaction, its structural basis for Kif2A recognition by WDR5 remains unclear. Here, we determine the crystal structure of WDR5 in complex with a Kif2A-derived peptide (residues 114-122) at a resolution of 1.85 Å. Structural analysis reveals that Kif2A engages both the WIN and S7 sites of WDR5 via Arg117 and Ser121, with Ser121 forming hydrogen bonds with WDR5 Tyr191 and Lys259, driving Tyr191 rotation and opening the S7 pocket. Additional structures of WDR5 complexed with truncated or mutated Kif2A peptides and a WDR5 Y191F variant highlight the dynamic nature of Tyr191. Notably, anti-WDR5 compounds exhibit a similar binding mode at the WDR5 WIN-S7 site. The results of mutagenesis combined with isothermal titration calorimetry (ITC) assays underscore the critical roles of Arg117 and Ser121 in mediating the binding of Kif2A to WDR5. In summary, our findings provide atomic-level insights into the molecular mechanisms underlying the non-canonical mitotic function of the MLL/WDR5 complex and highlight WIN-S7 sites as promising therapeutic targets for diseases associated with chromosomal instability, such as cancers.

PubMed: 40302551
DOI: 10.3724/abbs.2025066

Experimental method

X-RAY DIFFRACTION (1.8 Å)