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

Zyryanova, Alisa F.; Weis, F�lix; 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.; Ron, David

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


Authors

Alisa F. Zyryanova

F�lix Weis

Alexandre Faille

Akeel Abo Alard

Ana Crespillo-Casado

Yusuke Sekine

Heather P. Harding

Felicity Allen

Leopold Parts

Christoph Fromont

Peter M. Fischer

Alan J. Warren

David Ron



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.

Citation

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), https://doi.org/10.1126/science.aar5129

Journal Article Type Article
Acceptance Date Feb 9, 2018
Publication Date Mar 30, 2018
Deposit Date Apr 6, 2018
Publicly Available Date Mar 29, 2024
Journal Science
Print ISSN 0036-8075
Electronic ISSN 1095-9203
Publisher American Association for the Advancement of Science
Peer Reviewed Peer Reviewed
Volume 359
Issue 6383
DOI https://doi.org/10.1126/science.aar5129
Public URL https://nottingham-repository.worktribe.com/output/922354
Publisher URL http://science.sciencemag.org/content/359/6383/1533.long

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