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

View ORCID ProfileJoseph A Newman, Angeline E Gavard, Simone Lieb, Madhwesh C Ravichandran, Katja Hauer, Patrick Werni, Leonhard Geist, View ORCID ProfileJark Böttcher, View ORCID ProfileJohn R Engen, Klaus Rumpel, Matthias Samwer, View ORCID ProfileMark Petronczki, View ORCID ProfileOpher Gileadi  Correspondence email
Joseph A Newman
1Structural Genomics Consortium, University of Oxford, Oxford, UK
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Angeline E Gavard
1Structural Genomics Consortium, University of Oxford, Oxford, UK
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Simone Lieb
2Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
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Madhwesh C Ravichandran
2Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
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Katja Hauer
2Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
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Patrick Werni
2Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
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Leonhard Geist
2Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
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Jark Böttcher
2Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
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John R Engen
3Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, USA
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Klaus Rumpel
2Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
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Matthias Samwer
2Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
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Mark Petronczki
2Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
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Opher Gileadi
1Structural Genomics Consortium, University of Oxford, Oxford, UK
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  • For correspondence: opher.gileadi@cmd.ox.ac.uk
Published 16 November 2020. DOI: 10.26508/lsa.202000795
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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.

  • Received May 26, 2020.
  • Revision received October 28, 2020.
  • Accepted October 28, 2020.
  • © 2020 Newman et al.
Creative Commons logoCreative Commons logohttps://creativecommons.org/licenses/by/4.0/

This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).

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Crystal structure of Werner syndrome helicase core domain
Joseph A Newman, Angeline E Gavard, Simone Lieb, Madhwesh C Ravichandran, Katja Hauer, Patrick Werni, Leonhard Geist, Jark Böttcher, John R Engen, Klaus Rumpel, Matthias Samwer, Mark Petronczki, Opher Gileadi
Life Science Alliance Nov 2020, 4 (1) e202000795; DOI: 10.26508/lsa.202000795

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Crystal structure of Werner syndrome helicase core domain
Joseph A Newman, Angeline E Gavard, Simone Lieb, Madhwesh C Ravichandran, Katja Hauer, Patrick Werni, Leonhard Geist, Jark Böttcher, John R Engen, Klaus Rumpel, Matthias Samwer, Mark Petronczki, Opher Gileadi
Life Science Alliance Nov 2020, 4 (1) e202000795; DOI: 10.26508/lsa.202000795
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Volume 4, No. 1
January 2021
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