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

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Zyryanova, Alisa F., Weis, Félix, Faille, Alexandre, Abo Alard, Akeel, Crespillo-Casado, Ana, Sekine, Yusuke, Harding, Heather P., Allen, Felicity, Parts, Leopold, Fromont, Christoph, Fischer, Peter M., 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.

Item Type: Article
Schools/Departments: University of Nottingham, UK > Faculty of Science > School of Pharmacy
Identification Number: 10.1126/science.aar5129
Depositing User: Fischer, Professor Peter
Date Deposited: 06 Apr 2018 08:53
Last Modified: 30 Sep 2018 04:30
URI: https://eprints.nottingham.ac.uk/id/eprint/50909

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