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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 to single-stranded DNA (ssDNA), capturing key conformations in the helicase catalytic cycle. These structures reveal how WRN engages DNA through conserved polar and aromatic interactions, and how domain rearrangements, including an ordering of the aromatic-rich loop (ARL), drive directional translocation. Biochemical and biophysical data demonstrate how nucleotide and inhibitor binding remodel these conformations and suggest that known clinical inhibitors (HRO761 and VVD-133214) function by locking WRN in inactive, \u2018off-DNA\u2019 states. Resistance emerged rapidly in vitro, through acquired point mutations as well as altered WRN expression. Together, our findings provide a structural framework for the WRN structural cycle and support the development of next-generation \u2018on-DNA\u2019 inhibitors to overcome resistance.<\/jats:p>","DOI":"10.1038\/s42003-026-09584-0","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T21:36:31Z","timestamp":1769636191000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Structural insights into WRN helicase reveal conformational states and opportunities for MSI-H cancer drug discovery"],"prefix":"10.1038","volume":"9","author":[{"given":"Catherine T.","family":"Fletcher","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6616-8727","authenticated-orcid":false,"given":"Abigail A.","family":"Mornement","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Barrett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Canning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prakash","family":"Rucktooa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Huber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher D. 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