Loss of WRN, a DNA repair helicase, was identified as a strong vulnerability of microsatellite instable (MSI) cancers, making WRN a promising drug target. We show that ATP binding and hydrolysis are required for genome integrity and viability of MSI cancer cells. We report a 2.2-Å crystal structure of the WRN helicase core (517-1,093), comprising the two helicase subdomains and winged helix domain but not the HRDC domain or nuclease domains. The structure highlights unusual features. First, an atypical mode of nucleotide binding that results in unusual relative positioning of the two helicase subdomains. Second, an additional β-hairpin in the second helicase subdomain and an unusual helical hairpin in the Zn²⁺ binding domain. Modelling of the WRN helicase in complex with DNA suggests roles for these features in the binding of alternative DNA structures. NMR analysis shows a weak interaction between the HRDC domain and the helicase core, indicating a possible biological role for this association. Together, this study will facilitate the structure-based development of inhibitors against WRN helicase.

中文翻译：

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Werner解旋酶的解旋酶核心结构，微卫星不稳定性癌症的关键靶点。

WRN（一种 DNA 修复解旋酶）的缺失被确定为微卫星不稳定 (MSI) 癌症的一个强弱点，使 WRN 成为有希望的药物靶点。我们表明 ATP 结合和水解是 MSI 癌细胞的基因组完整性和活力所必需的。我们报告了 WRN 解旋酶核心 (517-1,093) 的 2.2 Å 晶体结构，包括两个解旋酶子域和翼状螺旋域，但不包括 HRDC 域或核酸酶域。该结构突出了不寻常的特征。首先，核苷酸结合的非典型模式导致两个解旋酶子域的异常相对定位。其次，第二个解旋酶亚域中的额外 β-发夹和 Zn ^{2+ 中}不寻常的螺旋发夹绑定域。WRN 解旋酶与 DNA 复合体的建模表明这些特征在结合替代 DNA 结构中的作用。核磁共振分析显示 HRDC 结构域和解旋酶核心之间的相互作用较弱，表明这种关联可能具有生物学作用。总之，这项研究将促进针对 WRN 解旋酶的抑制剂的基于结构的开发。