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. ORCID: https://orcid.org/0000-0002-8745-8377, 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:	04 May 2023 14:42
URI:	https://orca.cardiff.ac.uk/id/eprint/143165

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