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    3.9 Å structure of the yeast Mec1-Ddc2 complex, a homolog of human ATR-ATRIP.

    • Authors:
    • Xuejuan Wang
      Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences
      Tingting Ran
      Nanjing Agricultural University
      China
      Xuan Zhang
      Peking Union Medical College Hospital
      China
      Jiyu Xin
      Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences
      Hefei Shi | China
      Zhihui Zhang
      Florida State University
      China
      Tengwei Wu
      Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences
      Hefei Shi | China
      Weiwu Wang
      Laboratory of Molecular Microbiology
      Gang Cai
      Fudan University Shanghai Cancer Center
      China
    Science 2017 Dec;358(6367):1206-1209
    Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China.
    The ataxia telangiectasia-mutated and Rad3-related (ATR) kinase is a master regulator of DNA damage response and replication stress in humans, but the mechanism of its activation remains unclear. ATR acts together with its partner ATRIP. Using cryo-electron microscopy, we determined the structure of intact Mec1-Ddc2 (the yeast homolog of ATR-ATRIP), which is poised for catalysis, at a resolution of 3.9 angstroms. Mec1-Ddc2 forms a dimer of heterodimers through the PRD and FAT domains of Mec1 and the coiled-coil domain of Ddc2. The PRD and Bridge domains in Mec1 constitute critical regulatory sites. The activation loop of Mec1 is inhibited by the PRD, revealing an allosteric mechanism of kinase activation. Our study clarifies the architecture of ATR-ATRIP and provides a structural framework for the understanding of ATR regulation.
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