ArticleMolecular cell2021
ISRIB Blunts the Integrated Stress Response by Allosterically Antagonising the Inhibitory Effect of Phosphorylated eIF2 on eIF2B.
Article in Molecular cell, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 132 papers, 1 of them a synthesis that pooled it.
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Who cites it
132 citing papers in PubMed, 1 synthesis or guideline pooled it, 192 citations in OpenAlex.
- ER stress as a trigger of UPR and ER-phagy in cancer growth and spread.Frontiers in oncology · 2022Pooled it
- Translational dysregulation as a mechanistic driver of cognitive, behavioral, and affective phenotypes in FXS and TSC.Neuroscience and biobehavioral reviews · 2026Review
- Prion-Like Protein LENG8-Mediated Nucleation Drives Stress Granule Assembly.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Monovalent Nondegrading Molecular Glues: An Updated Overview of Emerging Mechanisms and Therapeutic Development.Pharmaceuticals (Basel, Switzerland) · 2026Review
- An axon-intrinsic loop restricts nerve regeneration through axonal protein synthesis.Science advances · 2026Article
- ATF4 orchestrates cancer hallmarks: Stress adaptation, metabolic reprogramming and immune suppression.iScience · 2026Review
- Structural Transformation of a BRAF Inhibitor into a Selective PKR Inhibitor.Journal of medicinal chemistry · 2026Article
- Allosteric disordering of eIF2B regulates the integrated stress response.Nature chemical biology · 2026Article
- Atypical Tetracyclines Promote Longevity and Ferroptotic Neuroprotection via Translation Attenuation.Aging cell · 2026Article
- Probiotic interventions maintain intestinal barrier function and alleviate necrotizing enterocolitis by inhibiting ferroptosis in intestinal PMN-MDSCs.Cell death & disease · 2026Article
- Elevated GCN2 levels in cancer cells confer protection from mitotic stress and faster cell movement.Cellular oncology (Dordrecht, Netherlands) · 2026Article
- A molecular stabiliser of an inhibitory eIF2B-eIF2(αP) complex activates the Integrated Stress Response.Nature communications · 2026Article
- The integrated stress response in cancer: mechanisms of tumor adaptation and therapeutic targeting.Biochemical Society transactions · 2026Review
- A GmeIF2B5-GmPRX4 Regulatory Axis Divergently Governs Drought-Lignin and Salt-Ion Homeostasis in Soybean.Plant biotechnology journal · 2026Article
- Article
- Stress granules as a central hub linking organelle stress, aging, and neurodegeneration.BMB reports · 2026Review
- Regulation of Translation of ATF4 mRNA: A Focus on Translation Initiation Factors and RNA-Binding Proteins.Cells · 2026Review
- Atypical tetracyclines promote longevity and ferroptotic neuroprotection via translation attenuation.bioRxiv : the preprint server for biology · 2026Article
- Integrated stress response inhibition prolongs the lifespan of a Pelizaeus-Merzbacher disease mouse model by increasing oligodendrocyte survival.Nature communications · 2025Article
- SPLiCR-seq: A CRISPR-Based Screening Platform for RNA splicing Identifies Novel Regulators of IRE1α-XBP1 Signaling Under ER Stress.Nature communications · 2025Article
72 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 2 institutions in 3 countries.
Funding
Abstract
The small molecule ISRIB antagonizes the activation of the integrated stress response (ISR) by phosphorylated translation initiation factor 2, eIF2(αP). ISRIB and eIF2(αP) bind distinct sites in their common target, eIF2B, a guanine nucleotide exchange factor for eIF2. We have found that ISRIB-mediated acceleration of eIF2B's nucleotide exchange activity in vitro is observed preferentially in the presence of eIF2(αP) and is attenuated by mutations that desensitize eIF2B to the inhibitory effect of eIF2(αP). ISRIB's efficacy as an ISR inhibitor in cells also depends on presence of eIF2(αP). Cryoelectron microscopy (cryo-EM) showed that engagement of both eIF2B regulatory sites by two eIF2(αP) molecules remodels both the ISRIB-binding pocket and the pockets that would engage eIF2α during active nucleotide exchange, thereby discouraging both binding events. In vitro, eIF2(αP) and ISRIB reciprocally opposed each other's binding to eIF2B. These findings point to antagonistic allostery in ISRIB action on eIF2B, culminating in inhibition of the ISR.
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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.