Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B

作者：Zyryanova Alisa F; Weis Felix; Faille Alexandre; Alard Akeel Abo; Crespillo Casado Ana; Sekine Yusuke; Harding Heather P; Allen Felicity; Parts Leopold; Fromont Christophe; Fischer Peter M; Warren Alan J^*; Ron David^*

来源：Science, 2018, 359(6383): 1533-1536.

DOI：10.1126/science.aar5129

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 2a (eIF2a) that attenuates the guanine nucleotide exchange factor eIF2B. A chemical inhibitor of the ISR, ISRIB, reverses the attenuation of eIF2B by phosphorylated eIF2a, 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 b and d 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.

• 出版日期2018-3-30
• 单位河北医科大学