Targeting lysine specific demethylase 4A (KDM4A) tandem TUDOR domain – A fragment based approach
2018
Abstract The tandem
TUDOR domainspresent in the non-catalytic C-terminal half of the KDM4A, 4B and 4C enzymes play important roles in regulating their chromatin localizations and substrate specificities. They achieve this regulatory role by binding to different tri-methylated lysine residues on
histone H3(H3-K4me3, H3-K23me3) and
histone H4(H4-K20me3) depending upon the specific chromatin environment. In this work, we have used a 2D-NMR based fragment screening approach to identify a novel fragment ( 1a ), which binds to the KDM4A-
TUDOR domainand shows modest competition with H3-K4me3 binding in biochemical as well as in vitro cell based assays. A co-crystal structure of KDM4A
TUDOR domainin complex with 1a shows that the fragment binds stereo-specifically to the methyl lysine binding pocket forming a network of strong hydrogen bonds and hydrophobic interactions. We anticipate that the fragment 1a can be further developed into a novel allosteric inhibitor of the KDM4 family of enzymes through targeting their C-terminal tandem
TUDOR domain.
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