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Binding of ISRIB Reveals a Regulatory Site in the Nucleotide Exchange Factor eIF2B

Binding of ISRIB Reveals a Regulatory Site in the Nucleotide Exchange Factor eIF2B

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

Science. 2018 Mar 30;359(6383):1533-1536.

PMID: 29599245

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4243666	ISRIB			Price

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