Open AccessUncovering an allosteric mode of action for a selective inhibitor of human Bloom syndrome protein
Author(s) -
Xiangrong Chen,
Yusuf Ali,
Charlotte E L Fisher,
Raquel Arribas-Bosacoma,
Mohan B. Rajasekaran,
Gareth Williams,
Sarah Walker,
Jessica R Booth,
Jessica Hudson,
S. Mark Roe,
Laurence H. Pearl,
Simon E. Ward,
Frances M. G. Pearl,
Antony W. Oliver
Publication year - 2021
Publication title -
elife
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.879
H-Index - 139
ISSN - 2050-084X
DOI - 10.7554/elife.65339
Subject(s) - helicase , holliday junction , bloom syndrome , allosteric regulation , dna , dna repair , biology , replication protein a , homologous recombination , biophysics , microbiology and biotechnology , drug discovery , dna damage , chemistry , genetics , biochemistry , dna binding protein , enzyme , gene , rna , transcription factor
BLM (Bloom syndrome protein) is a RECQ-family helicase involved in the dissolution of complex DNA structures and repair intermediates. 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. 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. 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. Comparison with structures of other RECQ helicases provides a model for branch migration of Holliday junctions by BLM.