PT  - JOURNAL ARTICLE
AU  - Newman, Joseph A
AU  - Gavard, Angeline E
AU  - Lieb, Simone
AU  - Ravichandran, Madhwesh C
AU  - Hauer, Katja
AU  - Werni, Patrick
AU  - Geist, Leonhard
AU  - Böttcher, Jark
AU  - Engen, John R
AU  - Rumpel, Klaus
AU  - Samwer, Matthias
AU  - Petronczki, Mark
AU  - Gileadi, Opher
TI  - Structure of the helicase core of Werner helicase, a key target in microsatellite instability cancers
AID  - 10.26508/lsa.202000795
DP  - 2021 Jan 01
TA  - Life Science Alliance
PG  - e202000795
VI  - 4
IP  - 1
4099  - http://www.life-science-alliance.org/content/4/1/e202000795.short
4100  - http://www.life-science-alliance.org/content/4/1/e202000795.full
SO  - Life Sci. Alliance2021 Jan 01; 4
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.