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Zyryanova, Alisa F. and Weis, Félix and Faille, Alexandre and Abo Alard, Akeel and Crespillo-Casado, Ana and Sekine, Yusuke and Harding, Heather P. and Allen, Felicity and Parts, Leopold and Fromont, Christoph and Fischer, Peter M. and Warren, Alan J. and Ron, David (2018) Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B. Science, 359 (6383). pp. 1533-1536. ISSN 1095-9203

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Abstract

The integrated stress response (ISR) is a conserved translational and transcriptional program affecting metabolism, memory, and immunity. The ISR is mediated by stress-induced phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) that attenuates the guanine nucleotide exchange factor eIF2B. A chemical inhibitor of the ISR, ISRIB, reverses the attenuation of eIF2B by phosphorylated eIF2α, protecting mice from neurodegeneration and traumatic brain injury. We describe a 4.1-angstrom-resolution cryo–electron microscopy structure of human eIF2B with an ISRIB molecule bound at the interface between the β and δ regulatory subunits. Mutagenesis of residues lining this pocket altered the hierarchical cellular response to ISRIB analogs in vivo and ISRIB binding in vitro. Our findings point to a site in eIF2B that can be exploited by ISRIB to regulate translation.

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