Structural insights into ISRIB, a memory‐enhancing inhibitor of the integrated stress response. (7th November 2019) - Anand, Aditya A.
Abstract : 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. Abstract : The decameric nucleotide exchange factor eIF2B [(αβγδε)2 ] exists in equilibrium with its subcomplexes: an α2 homodimer and two βγδε tetramers. The small molecule ISRIB enhances eIF2B exchange activity by stapling its tetrameric subcomplexes together across a twofold symmetry axis, promoting formation of the highly active decameric species.