Crystal Structure of the Werners Syndrome Helicase
| Autor: | Ravichandran Mc, Mark Petronczki, Matthias Samwer, Jark Böttcher, Klaus Rumpel, Opher Gileadi, Leonhard Geist, J.A. Newman, Engen, Katja Hauer, Patrick Werni, Angeline E Gavard, Simone Lieb |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
chemistry.chemical_classification
0303 health sciences education.field_of_study congenital hereditary and neonatal diseases and abnormalities biology Chemistry DNA repair Helicase nutritional and metabolic diseases Werner Syndrome Helicase Cell biology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cancer cell biology.protein Microsatellite Nucleotide education 030217 neurology & neurosurgery DNA 030304 developmental biology Binding domain |
| DOI: | 10.1101/2020.05.04.075176 |
| Popis: | Werner syndrome helicase (WRN) plays important roles in multiple pathways of DNA repair and the maintenance of genome integrity. Germline mutations in WRN give rise to Werner syndrome, a rare autosomal recessive progeroid syndrome that also features cancer predisposition. Interest in WRN as a therapeutic target has increased massively following the identification of WRN as the top synthetic lethal target for microsatellite instable (MSI) cancers. To this end several high throughput screens have identified candidate WRN helicase inhibitors although the structural information that would be necessary to progress these as true starting points for drug development is lacking. In this study we have further characterized the functions of WRN that are required for survival of MSI cancer cells, showing that ATP binding hydrolysis are required for complementation of siRNA-mediated WRN silencing. We determined the crystal structure of an ADP bound form of the WRN helicase core at 2.2 Å resolution. The structure features an atypical mode of nucleotide binding with extensive contacts formed by motif VI, which in turn defines the relative positioning of the two RecA like domains. The structure features a novel additional β-hairpin in the second RecA and an unusual helical hairpin in the Zn2+ binding domain, and modelling DNA substrates based on existing RecQ DNA complexes suggests roles for these features in the binding of alternative DNA structures. We have analysed the question of the role of the WRN HRDC domain and have used existing structures to examine possible interfaces formed from the interactions between the HRDC and helicase core. |
| Databáze: | OpenAIRE |
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