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Structure of the helicase core of Werner helicase, a key target in microsatellite instability cancers

DOI: 10.26508/lsa.202000795 DOI Help

Authors: Joseph A Newman (Structural Genomics Consortium, University of Oxford) , Angeline E. Gavard (Structural Genomics Consortium, University of Oxford) , Simone Lieb (Boehringer Ingelheim RCV GmbH & Co KG) , Madhwesh C. Ravichandran (Boehringer Ingelheim RCV GmbH & Co KG) , Katja Hauer (Boehringer Ingelheim RCV GmbH & Co KG) , Patrick Werni (Boehringer Ingelheim RCV GmbH & Co KG) , Leonhard Geist (Boehringer Ingelheim RCV GmbH & Co KG) , Jark Böttcher (Boehringer Ingelheim RCV GmbH & Co KG) , John R Engen (Northeastern University) , Klaus Rumpel (Boehringer Ingelheim RCV GmbH & Co KG) , Matthias Samwer (Boehringer Ingelheim RCV GmbH & Co KG) , Mark Petronczki (Boehringer Ingelheim RCV GmbH & Co KG) , Opher Gileadi (Structural Genomics Consortium, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Life Science Alliance , VOL 4

State: Published (Approved)
Published: November 2020
Diamond Proposal Number(s): 19301

Open Access Open Access

Abstract: 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.

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography

Added On: 14/12/2020 13:50

Documents:
e202000795.full.pdf

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)