Structural insights into WRN helicase reveal conformational states and opportunities for MSI-H cancer drug discovery.

Catherine T Fletcher¹, Abigail A Mornement¹, Charlotte Barrett¹, Peter Canning¹, Prakash Rucktooa¹, Sophie Huber¹, Christopher D O Cooper¹, Conor C G Scully¹, Andrew S Doré¹, Daniel Rohle¹, Geoffrey M T Smith¹, Sarah E Skerratt¹, Amanda J Kennedy²

¹CHARM Therapeutics Ltd., B900, Babraham Research Campus, Cambridge, UK.

²CHARM Therapeutics Ltd., B900, Babraham Research Campus, Cambridge, UK. amanda@charmtx.com.

PubMed PMC DOI PDF

Abstract

Werner syndrome helicase (WRN) is a RecQ-family DNA helicase essential for genome maintenance and is a synthetic lethal target in microsatellite instability-high (MSI-H) cancers. Despite its therapeutic promise, the conformational dynamics that enable WRN to unwind DNA, and how inhibitors disrupt this activity, remains poorly understood. Here, we present crystal structures of apo WRN and WRN bound…

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