4IA9

Crystal structure of human WD REPEAT DOMAIN 5 in complex with 2-chloro-4-fluoro-3-methyl-N-[2-(4-methylpiperazin-1-yl)-5-nitrophenyl]benzamide

4IA9 の概要

• エントリーDOI: 10.2210/pdb4ia9/pdb
• 分子名称: WD repeat-containing protein 5, 2-chloro-4-fluoro-3-methyl-N-[2-(4-methylpiperazin-1-yl)-5-nitrophenyl]benzamide, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: wdr5, structural genomics consortium, wd repeat domain 5, transcription, sgc
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus : P61964
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34820.86

構造登録者

Dong, A.,Dombrovski, L.,Bolshan, Y.,Getlik, M.,Tempel, W.,Kuznetsova, E.,Wasney, G.A.,Hajian, T.,Poda, G.,Nguyen, K.T.,Schapira, M.,Brown, P.J.,Al-awar, R.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.M.,Smil, D.,Vedadi, M.,Wu, H.,Structural Genomics Consortium (SGC) (登録日: 2012-12-06, 公開日: 2012-12-26, 最終更新日: 2023-09-20)

主引用文献

Bolshan, Y.,Getlik, M.,Kuznetsova, E.,Wasney, G.A.,Hajian, T.,Poda, G.,Nguyen, K.T.,Wu, H.,Dombrovski, L.,Dong, A.,Senisterra, G.,Schapira, M.,Arrowsmith, C.H.,Brown, P.J.,Al-Awar, R.,Vedadi, M.,Smil, D.
Synthesis, Optimization, and Evaluation of Novel Small Molecules as Antagonists of WDR5-MLL Interaction.
ACS Med Chem Lett, 4:353-357, 2013

PubMed Abstract: The WD40-repeat protein WDR5 plays a critical role in maintaining the integrity of MLL complexes and fully activating their methyltransferase function. MLL complexes, the trithorax-like family of SET1 methyltransferases, catalyze trimethylation of lysine 4 on histone 3, and they have been widely implicated in various cancers. Antagonism of WDR5 and MLL subunit interaction by small molecules has recently been presented as a practical way to inhibit activity of the MLL1 complex, and N-(2-(4-methylpiperazin-1-yl)-5-substituted-phenyl) benzamides were reported as potent and selective antagonists of such an interaction. Here, we describe the protein crystal structure guided optimization of prototypic compound 2 (K dis = 7 μM), leading to identification of more potent antagonist 47 (K dis = 0.3 μM).

PubMed: 24900672
DOI: 10.1021/ml300467n

実験手法

X-RAY DIFFRACTION (1.66 Å)