Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B

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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 b and d 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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Zyryanova, A. F., Weis, F., Faille, A., Abo Alard, A., Crespillo-Casado, A., Sekine, Y., … Ron, D. (2018). Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B. Science, 359(6383), 1533–1536. https://doi.org/10.1126/science.aar5129

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