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

Chen, X.; Ali, Y.; Fisher, C. E. L.; Arribas-Bosacoma, R.; Rajasekaran, M. B.; Williams, G.; Walker, S.; Roe, S. M.; Pearl, L. H.; Ward, S. E.; Pearl, F. M. G.; Oliver, A. W.

doi:10.1101/2020.11.30.403493

bioRxiv · 10.1101/2020.11.30.403493

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

Chen, X.·Ali, Y.·Fisher, C. E. L.·Arribas-Bosacoma, R.·Rajasekaran, M. B.·Williams, G.·Walker, S.·Roe, S. M.·Pearl, L. H.·Ward, S. E.·Pearl, F. M. G.·Oliver, A. W.

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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 BLMs 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.

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Chen, X., Ali, Y., Fisher, C. E. L., Arribas-Bosacoma, R., Rajasekaran, M. B., Williams, G., Walker, S., Roe, S. M., Pearl, L. H., Ward, S. E., Pearl, F. M. G., Oliver, A. W.. 2020-11-30. Uncovering an allosteric mode of action for a selective inhibitor of human Bloom syndrome protein. https://doi.org/10.1101/2020.11.30.403493

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