Mechanistic insights into phosphorylation-driven activation and therapeutic inhibition of human ATR-ATRIP. (PubMed, Nat Struct Mol Biol) - Sep 18, 2026 - "Here, we present high-resolution cryo-electron microscopy structures of the human ATR-ATRIP complex in distinct functional states, including two ATPγS-bound precatalytic states, a Chk1-bound catalytic state, a TopBP1-bound activated catalytic state and four inhibitor-bound states with gartisertib, berzosertib, ceralasertib and elimusertib. In addition, inhibitor-bound structures reveal how potent and selective ATR inhibition is achieved through multipocket engagement and exploitation of active-site conformational plasticity. Together, our findings provide a structural framework for understanding multiple routes of ATR activation and inhibition, offering insights for developing next-generation ATR-targeted cancer therapies."
Journal • Oncology • CHEK1 • TOPBP1
|
|
Boya Ma; Hao Wu; Jian Zheng; Jiangtao Guo; Jingdong Cheng; Jingwen Wang; Liang Zhao; Lingling Wang; Mo Wang; Qinhui Rao; Shuai Qiao; Yi Li; Youping Xu
|