Uncovering an allosteric mode of action for a selective inhibitor of human Bloom syndrome protein.
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Embargo End Date
ICR Authors
Authors
Chen, X
Ali, YI
Fisher, CE
Arribas-Bosacoma, R
Rajasekaran, MB
Williams, G
Walker, S
Booth, JR
Hudson, JJ
Roe, SM
Pearl, LH
Ward, SE
Pearl, FM
Oliver, AW
Ali, YI
Fisher, CE
Arribas-Bosacoma, R
Rajasekaran, MB
Williams, G
Walker, S
Booth, JR
Hudson, JJ
Roe, SM
Pearl, LH
Ward, SE
Pearl, FM
Oliver, AW
Document Type
Journal Article
Date
2021-03-01
Date Accepted
2021-02-16
Abstract
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.
Citation
eLife, 2021, 10
Source Title
Publisher
eLIFE SCIENCES PUBL LTD
ISSN
2050-084X
eISSN
2050-084X