7AUD

Structure of an engineered helicase domain construct for human Bloom syndrome protein (BLM)

Summary for 7AUD

• Entry DOI: 10.2210/pdb7aud/pdb
• Descriptor: Bloom syndrome protein,Bloom syndrome protein, DNA (5'-D(*GP*TP*AP*CP*CP*CP*GP*AP*TP*GP*TP*GP*T)-3'), ZINC ION, ... (8 entities in total)
• Functional Keywords: helicase, recq, blm, dna repair, inhibitor, allosteric, nuclear protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 12
• Total formula weight: 417975.02

Authors

Chen, X.,Oliver, A.W. (deposition date: 2020-11-02, release date: 2020-12-16, Last modification date: 2025-10-01)

Primary citation

Chen, X.,Ali, Y.I.,Fisher, C.E.,Arribas-Bosacoma, R.,Rajasekaran, M.B.,Williams, G.,Walker, S.,Booth, J.R.,Hudson, J.J.,Roe, S.M.,Pearl, L.H.,Ward, S.E.,Pearl, F.M.,Oliver, A.W.
Uncovering an allosteric mode of action for a selective inhibitor of human Bloom syndrome protein.
Elife, 10:-, 2021

PubMed 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.

PubMed: 33647232
DOI: 10.7554/eLife.65339

Experimental method

X-RAY DIFFRACTION (2.96 Å)