Uncovering an allosteric mode of action for a selective inhibitor of human Bloom syndrome protein

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 in...

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Bibliographic Details
Published in:	eLife Vol. 10
Main Authors:	Chen, Xiangrong, Ali, Yusuf I, Fisher, Charlotte El, Arribas-Bosacoma, Raquel, Rajasekaran, Mohan B, Williams, Gareth, Walker, Sarah, Booth, Jessica R, Hudson, Jessica Jr, Roe, S Mark, Pearl, Laurence H, Ward, Simon E, Pearl, Frances Mg, Oliver, Antony W
Format:	Journal Article
Language:	English
Published:	England eLife Sciences Publications Ltd 01-03-2021 eLife Sciences Publications, Ltd
Subjects:	Adenosine triphosphatase allosteric Allosteric properties Binding sites Biochemistry and Chemical Biology Bloom syndrome Bloom's syndrome Confidence intervals Deoxyribonucleic acid DNA DNA - metabolism DNA damage DNA helicase DNA repair DNA, Cruciform DNA, Single-Stranded Drug Discovery Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Escherichia coli Helicase High-Throughput Screening Assays Holliday junctions Humans inhibitor Intermediates Lethality RECQ RecQ Helicases - antagonists & inhibitors RecQ Helicases - metabolism RecQ protein Small Molecule Libraries - chemistry Small Molecule Libraries - pharmacology Structural Biology and Molecular Biophysics Visual aids Helicase Bloom syndrome allosteric chemical biology inhibitor RECQ biochemistry structural biology molecular biophysics DNA repair human E. coli
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2050-084X 2050-084X
DOI:	10.7554/eLife.65339