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.