elife-65339-v1.pdf (3.53 MB)
Uncovering an allosteric mode of action for a selective inhibitor of human Bloom syndrome protein
journal contribution
posted on 2023-06-09, 23:32 authored by Xiangrong Chen, Yusuf I Ali, Charlotte Emily Louise Fisher, Raquel Arribas, Mohan RajasekaranMohan Rajasekaran, Gareth Williams, Sarah Walker, Jessica BoothJessica Booth, Jessica HudsonJessica Hudson, S Mark Roe, Laurence PearlLaurence Pearl, Simon E Ward, Frances PearlFrances Pearl, Antony OliverAntony OliverBLM (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.
Funding
Structural Biology of DNA Damage Response and Repair Mechanisms; G2176; CANCER RESEARCH UK; C302/A24386
History
Publication status
- Published
File Version
- Published version
Journal
eLifeISSN
2050-084XPublisher
eLife Sciences PublicationsExternal DOI
Volume
10Page range
1-32Article number
a65339Event location
EnglandDepartment affiliated with
- Biochemistry Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2021-04-09First Open Access (FOA) Date
2021-04-09First Compliant Deposit (FCD) Date
2021-04-09Usage metrics
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