RT Journal Article SR Electronic T1 Structure of the helicase core of Werner helicase, a key target in microsatellite instability cancers JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202000795 DO 10.26508/lsa.202000795 VO 4 IS 1 A1 Newman, Joseph A A1 Gavard, Angeline E A1 Lieb, Simone A1 Ravichandran, Madhwesh C A1 Hauer, Katja A1 Werni, Patrick A1 Geist, Leonhard A1 Böttcher, Jark A1 Engen, John R A1 Rumpel, Klaus A1 Samwer, Matthias A1 Petronczki, Mark A1 Gileadi, Opher YR 2021 UL https://www.life-science-alliance.org/content/4/1/e202000795.abstract AB 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.