The Polycomb Repressive Complex 2 (PRC2) is a chromatin-associated methyltransferase that catalyzes the methylation of lysine 27 on histone H3 (Laugesen et al., 2019). The core subunits of PRC2 include SUZ12, EED, and the catalytic methyltransferase EZH2 or its closely related homolog (Laugesen et al., 2019). This research focuses on Enhancer of Zeste Homolog 2 (EZH2), a histone-lysine N-methyltransferase enzyme whose mutation or overexpression has been linked to numerous cancers (Li et al., 2021).
Using computational modeling to identify key stabilizing residues and simulate peptide–protein interactions, this project aims to design peptidomimetic inhibitors targeting EZH2. The models identified W15, R18, and Y23 as critical residues for stabilizing the interaction domain. Mutations at these positions disrupt EZH2 activity, indicating these sites are key in reducing its gene-silencing function. Overall, this work supports the development of targeted cancer therapeutics by establishing a computational framework for drug design.
References:
Laugesen, A., Højfeldt, J. W., & Helin, K. (2019). Molecular mechanisms directing PRC2 recruitment and H3K27 methylation. Molecular Cell, 74(1), 8–18. https://doi.org/10.1016/j.molcel.2019.03.011
Li, T., Yu, C., & Zhuang, S. (2021). Histone methyltransferase EZH2: A potential therapeutic target for kidney diseases. Frontiers in Physiology, 12, 640700. https://doi.org/10.3389/fphys.2021.640700