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

DOI: 10.7554/eLife.65339 DOI Help

Authors: Xiangrong Chen (University of Sussex) , Yusuf I Ali (University of Sussex) , Charlotte E. L. Fisher (University of Sussex) , Raquel Arribas-Bosacoma (University of Sussex) , Mohan B. Rajasekaran (University of Sussex) , Gareth Williams (University of Sussex) , Sarah Walker (University of Sussex) , Jessica R. Booth (University of Sussex) , Jessica J R. Hudson (University of Sussex) , S. Mark Roe (University of Sussex) , Laurence H. Pearl (University of Sussex) , Simon E. Ward (University of Sussex; Cardiff University) , Frances M G. Pearl (University of Sussex) , Antony W. Oliver (University of Sussex)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Elife , VOL 10

State: Published (Approved)
Published: March 2021
Diamond Proposal Number(s): 20145

Open Access Open Access

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.

Diamond Keywords: Bloom Syndrome

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Documents:
elife-65339-v1.pdf

Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Drug Discovery Non-Communicable Diseases Structural biology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)