![]() ![]() ( B) Quantification of inhibitory activity by 2 in the gel-based activity assay. ( A) Titration of BLM-HD with 2 prevents the unwinding of a forked-50mer dsDNA substrate into its component strands, as judged by native gel electrophoresis. coli Helicase RECQ allosteric biochemistry chemical biology human inhibitor molecular biophysics structural biology. ![]() Comparison with structures of other RECQ helicases provides a model for branch migration of Holliday junctions by BLM.īloom syndrome DNA repair E. Crystallographic structures of BLM-DNA-ADP-inhibitor complexes identify a hitherto unknown interdomain interface, whose opening and closing are integral to translocation of ssDNA, and which provides a highly selective pocket for drug discovery. Here, we identify and characterise a specific inhibitor of BLM's ATPase-coupled DNA helicase activity, by allosteric trapping of a DNA-bound translocation intermediate. Synthetic lethality analysis implicates BLM as a promising target in a range of cancers with defects in the DNA damage response however, selective small molecule inhibitors of defined mechanism are currently lacking. ![]() BLM (Bloom syndrome protein) is a RECQ-family helicase involved in the dissolution of complex DNA structures and repair intermediates. ![]()
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