The integrated stress response (ISR) regulates protein synthesis under conditions of stress. Phosphorylation of translation initiation factor eIF2 by stress-sensing kinases converts eIF2 from substrate to competitive inhibitor of its dedicated nucleotide exchange factor, eIF2B, arresting translation. A drug-like molecule called integrated stress response inhibitor (ISRIB) reverses the effects of eIF2 phosphorylation and restores translation by targeting eIF2B. When administered to mice, ISRIB enhances cognition and limits cognitive decline due to brain injury. To determine ISRIB's mechanism of action, we solved an atomic structure of ISRIB bound to the human eIF2B decamer. We found that ISRIB acts as a molecular staple, pinning together tetrameric subcomplexes of eIF2B along the assembly path to a fully active, decameric enzyme. In this Structural Snapshot, we discuss ISRIB's mechanism, its ability to rescue disease mutations in eIF2B and conservation of the enzyme and ISRIB-binding pocket.

中文翻译：

---

对ISRIB的结构见解，ISRIB是综合应激反应的记忆增强抑制剂。

整合的应激反应（ISR）调节应激条件下的蛋白质合成。应激感应激酶将翻译起始因子eIF2磷酸化，将eIF2从底物转化为其专用核苷酸交换因子eIF2B的竞争性抑制剂，从而阻止翻译。称为整合应激反应抑制剂（ISRIB）的类药物分子可逆转eIF2磷酸化的作用，并通过靶向eIF2B恢复翻译。当给小鼠服用时，ISRIB增强了认知能力并限制了由于脑损伤引起的认知能力下降。为了确定ISRIB的作用机理，我们解决了与人类eIF2B骗子绑定的ISRIB的原子结构。我们发现ISRIB充当分子的主要组成部分，沿着装配路径将eIF2B的四聚体亚复合体固定在一个完全活性的十聚体酶上。