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. a65339 1-32. ISSN 2050-084X

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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
Keywords: Bloom syndrome, DNA repair, E. coli, Helicase, RECQ, allosteric, biochemistry, chemical biology, human, inhibitor, molecular biophysics, structural biology
Schools and Departments: School of Life Sciences > Biochemistry
School of Life Sciences > Sussex Centre for Genome Damage and Stability
SWORD Depositor: Mx Elements Account
Depositing User: Mx Elements Account
Date Deposited: 09 Apr 2021 06:53
Last Modified: 09 Apr 2021 07:00
URI: http://sro.sussex.ac.uk/id/eprint/98319

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