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TitleBinding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B.
Journal, issue, pagesScience, Vol. 359, Issue 6383, Page 1533-1536, Year 2018
Publish dateMar 30, 2018
AuthorsAlisa 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 / David Ron /
PubMed AbstractThe 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 ...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.
External linksScience / PubMed:29599245 / PubMed Central
MethodsEM (single particle)
Resolution4.1 Å
Structure data

4162

6ezo

EMDB-4162, PDB-6ezo:
Eukaryotic initiation factor EIF2B in complex with ISRIB
Method: EM (single particle) / Resolution: 4.1 Å

Chemicals

ChemComp-C7B:
2-(4-chloranylphenoxy)-~{N}-[4-[2-(4-chloranylphenoxy)ethanoylamino]cyclohexyl]ethanamide / ISRIB

Source
  • homo sapiens (human)
  • human (human)
KeywordsMEMBRANE PROTEIN / GEF / Complex / ISRIB

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