9S1A
WRN helicase in the absence of nucleotide or DNA
Summary for 9S1A
| Entry DOI | 10.2210/pdb9s1a/pdb |
| Related | 9S17 9S18 9S19 |
| Descriptor | Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN, ZINC ION, SULFATE ION, ... (7 entities in total) |
| Functional Keywords | inhibitor, covalent, helicase, allosteric, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 98642.24 |
| Authors | |
| Primary citation | Fletcher, C.T.,Mornement, A.A.,Barrett, C.,Canning, P.,Rucktooa, P.,Huber, S.,Cooper, C.D.O.,Scully, C.C.G.,Dore, A.S.,Rohle, D.,Smith, G.M.T.,Skerratt, S.E.,Kennedy, A.J. Structural insights into WRN helicase reveal conformational states and opportunities for MSI-H cancer drug discovery. Commun Biol, 9:-, 2026 Cited by PubMed 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 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, 'off-DNA' 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 'on-DNA' inhibitors to overcome resistance. PubMed: 41606312DOI: 10.1038/s42003-026-09584-0 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.956 Å) |
Structure validation
Download full validation report
