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

Chen, Xiangrong, Ali, Yusuf I., Fisher, Charlotte E. L., Arribas-Bosacoma, Raquel, Rajasekaran, Mohan B., Williams, Gareth, Walker, Sarah, Booth, Jessica R., Hudson, Jessica J. R., Roe, S. Mark, Pearl, Laurence H., Ward, Simon E., Pearl, Frances M. G. and Oliver, Antony W. 2021. Uncovering an allosteric mode of action for a selective inhibitor of human Bloom syndrome protein. eLife 10 , e65339. 10.7554/eLife.65339

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Biosciences Neuroscience and Mental Health Research Institute (NMHRI)
Publisher:	eLife Sciences Publications
ISSN:	2050-084X
Date of First Compliant Deposit:	4 August 2021
Date of Acceptance:	16 February 2021
Last Modified:	16 Aug 2021 14:15
URI:	https://orca.cardiff.ac.uk/id/eprint/143165

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