6EZO

Eukaryotic initiation factor EIF2B in complex with ISRIB

Summary for 6EZO

• Entry DOI: 10.2210/pdb6ezo/pdb
• Related: 5b04
• EMDB information: 4162
• Descriptor: Translation initiation factor eIF-2B subunit alpha, Translation initiation factor eIF-2B subunit beta, Translation initiation factor eIF-2B subunit gamma, ... (6 entities in total)
• Functional Keywords: gef, complex, isrib, membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 10
• Total formula weight: 528298.14

Authors

Faille, A.,Weis, F.,Zyryanova, A.,Warren, A.J.,Ron, D. (deposition date: 2017-11-16, release date: 2018-03-28, Last modification date: 2024-05-15)

Primary citation

Zyryanova, A.F.,Weis, F.,Faille, A.,Alard, A.A.,Crespillo-Casado, A.,Sekine, Y.,Harding, H.P.,Allen, F.,Parts, L.,Fromont, C.,Fischer, P.M.,Warren, A.J.,Ron, D.
Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B.
Science, 359:1533-1536, 2018

PubMed 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.

PubMed: 29599245
DOI: 10.1126/science.aar5129

Experimental method

ELECTRON MICROSCOPY (4.1 Å)