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Updated: Feb 12, 2026

Measuring Nucleotide Binding to Intact, Functional Membrane Proteins in Real Time
Published on: March 11, 2021
Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B
Alisa F Zyryanova1, Félix Weis2,3,4,5, Alexandre Faille2,3,4
1Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK. az310@cam.ac.uk ajw1000@cam.ac.uk dr360@medschl.cam.ac.uk.
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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