Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B
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 facto...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Association for the Advancement of Science
2018
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| Online Access: | https://eprints.nottingham.ac.uk/50909/ |
| _version_ | 1848798365962207232 |
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| author | Zyryanova, Alisa F. Weis, Félix Faille, Alexandre Abo Alard, Akeel Crespillo-Casado, Ana Sekine, Yusuke Harding, Heather P. Allen, Felicity Parts, Leopold Fromont, Christoph Fischer, Peter M. Warren, Alan J. Ron, David |
| author_facet | Zyryanova, Alisa F. Weis, Félix Faille, Alexandre Abo Alard, Akeel Crespillo-Casado, Ana Sekine, Yusuke Harding, Heather P. Allen, Felicity Parts, Leopold Fromont, Christoph Fischer, Peter M. Warren, Alan J. Ron, David |
| author_sort | Zyryanova, Alisa F. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T20:18:37Z |
| format | Article |
| id | nottingham-50909 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T20:18:37Z |
| publishDate | 2018 |
| publisher | American Association for the Advancement of Science |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-509092018-09-30T04:30:14Z https://eprints.nottingham.ac.uk/50909/ Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B Zyryanova, Alisa F. Weis, Félix Faille, Alexandre Abo Alard, Akeel Crespillo-Casado, Ana Sekine, Yusuke Harding, Heather P. Allen, Felicity Parts, Leopold Fromont, Christoph Fischer, Peter M. Warren, Alan J. Ron, David 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. American Association for the Advancement of Science 2018-03-30 Article PeerReviewed application/pdf en https://eprints.nottingham.ac.uk/50909/1/Zyryanova%2C%20A.F.%20et%20al.%20Science%202018%20author%20version.pdf Zyryanova, Alisa F., Weis, Félix, Faille, Alexandre, Abo Alard, Akeel, Crespillo-Casado, Ana, Sekine, Yusuke, Harding, Heather P., Allen, Felicity, Parts, Leopold, Fromont, Christoph, Fischer, Peter M., Warren, Alan J. and Ron, David (2018) Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B. Science, 359 (6383). pp. 1533-1536. ISSN 1095-9203 http://science.sciencemag.org/content/359/6383/1533.long doi:10.1126/science.aar5129 doi:10.1126/science.aar5129 |
| spellingShingle | Zyryanova, Alisa F. Weis, Félix Faille, Alexandre Abo Alard, Akeel Crespillo-Casado, Ana Sekine, Yusuke Harding, Heather P. Allen, Felicity Parts, Leopold Fromont, Christoph Fischer, Peter M. Warren, Alan J. Ron, David Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B |
| title | Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B |
| title_full | Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B |
| title_fullStr | Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B |
| title_full_unstemmed | Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B |
| title_short | Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B |
| title_sort | binding of isrib reveals a regulatory site in the nucleotide exchange factor eif2b |
| url | https://eprints.nottingham.ac.uk/50909/ https://eprints.nottingham.ac.uk/50909/ https://eprints.nottingham.ac.uk/50909/ |