9S19

WRN helicase in complex with ATPgS and ssDNA

9S19 の概要

• エントリーDOI: 10.2210/pdb9s19/pdb
• 関連するPDBエントリー: 9S17 9S18
• 分子名称: Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN, DNA (5'-D(P*TP*AP*CP*CP*C)-3'), ZINC ION, ... (7 entities in total)
• 機能のキーワード: inhibitor, covalent, helicase, allosteric, hydrolase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 108362.38

構造登録者

Fletcher, C.T.,Rucktooa, P. (登録日: 2025-07-18, 公開日: 2026-05-27)

主引用文献

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

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: 41606312
DOI: 10.1038/s42003-026-09584-0

実験手法

X-RAY DIFFRACTION (2.3 Å)