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

Summary for 4IA9

• Entry DOI: 10.2210/pdb4ia9/pdb
• Descriptor: 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)
• Functional Keywords: wdr5, structural genomics consortium, wd repeat domain 5, transcription, sgc
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus : P61964
• Total number of polymer chains: 1
• Total formula weight: 34820.86

Authors

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) (deposition date: 2012-12-06, release date: 2012-12-26, Last modification date: 2023-09-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.66 Å)