ArticleNature chemical biology2024
A helical fulcrum in eIF2B coordinates allosteric regulation of stress signaling.
Article in Nature chemical biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
What it found
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
7 citing papers in PubMed, 8 citations in OpenAlex.
- Allosteric disordering of eIF2B regulates the integrated stress response.Nature chemical biology · 2026Article
- A molecular stabiliser of an inhibitory eIF2B-eIF2(αP) complex activates the Integrated Stress Response.Nature communications · 2026Article
- Function and regulation of the mitochondrial stress response.Nature structural & molecular biology · 2026Review
- Termination of the integrated stress response.Science (New York, N.Y.) · 2026Article
- Targeting the unfolded protein response in cancer: mechanisms, small-molecule inhibitors, and translational challenges.Frontiers in immunology · 2026Review
- Case Report: New genetic variant and widely different phenotypes observed in twins with Vanishing White Matter disease.Frontiers in pediatrics · 2025Article
- Switching on stress.Nature chemical biology · 2024Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
The integrated stress response (ISR) enables cells to survive a variety of acute stresses, but chronic activation of the ISR underlies age-related diseases. ISR signaling downregulates translation and activates expression of stress-responsive factors that promote return to homeostasis and is initiated by inhibition of the decameric guanine nucleotide exchange factor eIF2B. Conformational and assembly transitions regulate eIF2B activity, but the allosteric mechanisms controlling these dynamic transitions and mediating the therapeutic effects of the small-molecule ISR inhibitor ISRIB are unknown. Using hydrogen-deuterium exchange-mass spectrometry and cryo-electron microscopy, we identified a central α-helix whose orientation allosterically coordinates eIF2B conformation and assembly. Biochemical and cellular signaling assays show that this 'switch-helix' controls eIF2B activity and signaling. In sum, the switch-helix acts as a fulcrum of eIF2B conformational regulation and is a highly conserved actuator of ISR signal transduction. This work uncovers a conserved allosteric mechanism and unlocks new therapeutic possibilities for ISR-linked diseases.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.