7aud
Structure of an engineered helicase domain construct for human Bloom syndrome protein (BLM)
Structural highlights
DiseaseBLM_HUMAN Bloom syndrome. The disease is caused by mutations affecting the gene represented in this entry. FunctionBLM_HUMAN Participates in DNA replication and repair. Exhibits a magnesium-dependent ATP-dependent DNA-helicase activity that unwinds single- and double-stranded DNA in a 3'-5' direction. Involved in 5'-end resection of DNA during double-strand break (DSB) repair: unwinds DNA and recruits DNA2 which mediates the cleavage of 5'-ssDNA. Negatively regulates sister chromatid exchange (SCE).[1] [2] [3] [4] Publication Abstract from PubMedBLM (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. Uncovering an allosteric mode of action for a selective inhibitor of human Bloom syndrome protein.,Chen X, Ali YI, Fisher CE, Arribas-Bosacoma R, Rajasekaran MB, Williams G, Walker S, Booth JR, Hudson JJ, Roe SM, Pearl LH, Ward SE, Pearl FM, Oliver AW Elife. 2021 Mar 1;10. pii: 65339. doi: 10.7554/eLife.65339. PMID:33647232[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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