9CUX

Crystal Structure of SETDB1 Tudor domain in complex with UNC100016

これはPDB形式変換不可エントリーです。

9CUX の概要

• エントリーDOI: 10.2210/pdb9cux/pdb
• 分子名称: 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)
• 機能のキーワード: tudor domain, setdb1, sgc, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 27571.78

構造登録者

Silva, M.,Dong, A.,Arrowsmith, C.H.,Edwards, A.M.,Halabelian, L.,Structural Genomics Consortium (SGC) (登録日: 2024-07-26, 公開日: 2024-10-02, 最終更新日: 2025-10-22)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.27 Å)