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Updated: Jan 10, 2026
Specificity Analysis of Protein Lysine Methyltransferases Using SPOT Peptide Arrays
Published on: November 29, 2014
Fragment-Based Screening of NSD2-PWWP1 Identifies Novel Covalent Allosteric Ligands That Diminish Methyllysine and
Yunyuan Huang1, Yanxi Li1, Xin Chen2
1Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan 430079, China.
Abstract:
The PWWP1 domain of NSD2 recognizes both H3K36me2/3 and DNA, a function critical for its subcellular localization and oncogenic activity, making it a promising therapeutic target. In this study, through fragment library screening and structure-activity relationship studies, we identified compounds that covalently bind to the C294 residue of NSD2-PWWP1. Structural and biochemical analyses demonstrated that compounds 13 and 16 competitively block NSD2-PWWP1's recognition of both H3K36me2 and DNA, thereby impairing its nucleosome-binding ability. This study uncovers a novel allosteric regulatory mechanism and provides a structural framework for the development of more effective cancer therapeutics targeting NSD2-PWWP1.
