Journal: Science / Year: 2018 Title: Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B. 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 ...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 / 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.
Mass: 41758.242 Da / Num. of mol.: 2 Mutation: 3xFLAG inserted at position +4 of the protein sequence Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Tissue: cervix / Cell line: epithelial / Gene: EIF2B2, EIF2BB / Plasmid: HeLa-2C2 / Cell line (production host): HeLa / Production host: Homo sapiens (human) / References: UniProt: P49770
Average exposure time: 1.5 sec. / Electron dose: 30 e/Å2 / Detector mode: INTEGRATING / Film or detector model: FEI FALCON II (4k x 4k) / Num. of real images: 765