9CUX

Crystal Structure of SETDB1 Tudor domain in complex with UNC100016

This is a non-PDB format compatible entry.

Summary for 9CUX

• Entry DOI: 10.2210/pdb9cux/pdb
• Descriptor: Histone-lysine N-methyltransferase SETDB1, (2E)-N-(4-{[6-(dimethylamino)hexyl]amino}-2-{[5-(dimethylamino)pentyl]amino}quinazolin-6-yl)but-2-enamide, SULFATE ION, ... (6 entities in total)
• Functional Keywords: tudor domain, setdb1, sgc, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 27571.78

Authors

Silva, M.,Dong, A.,Arrowsmith, C.H.,Edwards, A.M.,Halabelian, L.,Structural Genomics Consortium (SGC) (deposition date: 2024-07-26, release date: 2024-10-02, Last modification date: 2025-10-22)

Primary citation

Uguen, M.,Shell, D.J.,Silva, M.,Deng, Y.,Li, F.,Szewczyk, M.M.,Yang, K.,Zhao, Y.,Stashko, M.A.,Norris-Drouin, J.L.,Waybright, J.M.,Beldar, S.,Rectenwald, J.M.,Mordant, A.L.,Webb, T.S.,Herring, L.E.,Arrowsmith, C.H.,Ackloo, S.,Gygi, S.P.,McGinty, R.K.,Barsyte-Lovejoy, D.,Liu, P.,Halabelian, L.,James, L.I.,Pearce, K.H.,Frye, S.V.
Potent and selective SETDB1 covalent negative allosteric modulator reduces methyltransferase activity in cells.
Nat Commun, 16:1905-1905, 2025

PubMed Abstract: A promising drug target, SETDB1, is a dual methyl-lysine (Kme) reader and methyltransferase implicated in cancer and neurodegenerative disease progression. To help understand the role of the triple Tudor domain (3TD) of SETDB1, its Kme reader, we first identify a low micromolar potency small molecule ligand, UNC6535, which occupies simultaneously both the TD2 and TD3 reader binding sites. Further optimization leads to the discovery of UNC10013, a covalent 3TD ligand targeting Cys385 of SETDB1. UNC10013 is potent with a k/K of 1.0 × 10 Ms and demonstrates proteome-wide selectivity. In cells, negative allosteric modulation of SETDB1-mediated Akt methylation occurs after treatment with UNC10013. Therefore, UNC10013 is a potent, selective, and cell-active covalent ligand for the 3TD of SETDB1, demonstrating negative allosteric modulator properties and making it a promising tool to study the biological role of SETDB1 in disease progression.

PubMed: 39994194
DOI: 10.1038/s41467-025-57005-3

Experimental method

X-RAY DIFFRACTION (1.27 Å)