Cancer Research UK DNA Repair Enzymes Group, Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, United Kingdom.
Bioinformatics Lab, School of Life Sciences, University of Sussex, Falmer, United Kingdom.
Elife. 2021 Mar 1;10:e65339. doi: 10.7554/eLife.65339.
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.
BLM（布鲁姆综合征蛋白）是一种 RECQ 家族解旋酶，参与复杂 DNA 结构和修复中间体的溶解。合成致死性分析表明，BLM 是 DNA 损伤反应缺陷的多种癌症中有前途的靶点；然而，目前缺乏具有明确机制的选择性小分子抑制剂。在这里，我们通过 DNA 结合的转位中间产物的别构捕获，鉴定并表征了 BLM 的 ATP 酶偶联 DNA 解旋酶活性的特异性抑制剂。BLM-DNA-ADP-抑制剂复合物的晶体结构确定了一个以前未知的结构域间界面，其打开和关闭是 ssDNA 转位的组成部分，并且为药物发现提供了一个高度选择性的口袋。与其他 RECQ 解旋酶的结构比较为 BLM 进行 Holliday 结的分支迁移提供了模型。
