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-Structure paper
Title | Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B. |
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Journal, issue, pages | Science, Vol. 359, Issue 6383, Page 1533-1536, Year 2018 |
Publish date | Mar 30, 2018 |
Authors | 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 / David Ron / |
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 ...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 links | Science / PubMed:29599245 / PubMed Central |
Methods | EM (single particle) |
Resolution | 4.1 Å |
Structure data | |
Chemicals | ChemComp-C7B: |
Source |
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Keywords | MEMBRANE PROTEIN / GEF / Complex / ISRIB |