6UE6

PWWP1 domain of NSD2 in complex with MR837

Summary for 6UE6

• Entry DOI: 10.2210/pdb6ue6/pdb
• Descriptor: Histone-lysine N-methyltransferase NSD2, 4-cyano-N-cyclopropyl-N-[(thiophen-2-yl)methyl]benzamide, UNKNOWN ATOM OR ION (3 entities in total)
• Functional Keywords: methyltransferase, structural genomics, structural genomics consortium, sgc, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 8
• Total formula weight: 130790.79

Authors

Liu, Y.,Tempel, W.,De Freitas, R.F.,Schapira, M.,Brown, P.J.,Bountra, C.,Edwards, A.M.,Arrowsmith, C.H.,Min, J.,Structural Genomics Consortium (SGC) (deposition date: 2019-09-20, release date: 2019-11-13, Last modification date: 2023-10-11)

Primary citation

Ferreira de Freitas, R.,Liu, Y.,Szewczyk, M.M.,Mehta, N.,Li, F.,McLeod, D.,Zepeda-Velazquez, C.,Dilworth, D.,Hanley, R.P.,Gibson, E.,Brown, P.J.,Al-Awar, R.,James, L.I.,Arrowsmith, C.H.,Barsyte-Lovejoy, D.,Min, J.,Vedadi, M.,Schapira, M.,Allali-Hassani, A.
Discovery of Small-Molecule Antagonists of the PWWP Domain of NSD2.
J.Med.Chem., 64:1584-1592, 2021

PubMed Abstract: Increased activity of the lysine methyltransferase NSD2 driven by translocation and activating mutations is associated with multiple myeloma and acute lymphoblastic leukemia, but no NSD2-targeting chemical probe has been reported to date. Here, we present the first antagonists that block the protein-protein interaction between the N-terminal PWWP domain of NSD2 and H3K36me2. Using virtual screening and experimental validation, we identified the small-molecule antagonist , which binds to the NSD2-PWWP1 domain with a of 3.4 μM and abrogates histone H3K36me2 binding to the PWWP1 domain in cells. This study establishes an alternative approach to targeting NSD2 and provides a small-molecule antagonist that can be further optimized into a chemical probe to better understand the cellular function of this protein.

PubMed: 33522809
DOI: 10.1021/acs.jmedchem.0c01768

Experimental method

X-RAY DIFFRACTION (2.4 Å)