9KNB

NSD2-PWWP1 domain bound with compound 9

This is a non-PDB format compatible entry.

Summary for 9KNB

• Entry DOI: 10.2210/pdb9knb/pdb
• Descriptor: Histone-lysine N-methyltransferase NSD2, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, N-(2-methoxyphenyl)-2-selanyl-benzamide, ... (4 entities in total)
• Functional Keywords: pwwp, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 15785.16

Authors

Huang, Y.,Li, Y.,Min, J. (deposition date: 2024-11-18, release date: 2025-11-26, Last modification date: 2025-12-24)

Primary citation

Huang, Y.,Li, Y.,Chen, X.,Wang, H.,Wang, Q.,Liu, S.,Li, Y.,Chen, Z.,Ma, J.,Huang, Z.,Wan, J.,Ren, Y.,Min, J.
Fragment-Based Screening of NSD2-PWWP1 Identifies Novel Covalent Allosteric Ligands That Diminish Methyllysine and DNA Binding Abilities of NSD2.
J.Med.Chem., 68:24953-24967, 2025

PubMed 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 and 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.

PubMed: 41264880
DOI: 10.1021/acs.jmedchem.5c01902

Experimental method

X-RAY DIFFRACTION (1.84 Å)