ArticleNature communications2020
Activation of the IRE1 RNase through remodeling of the kinase front pocket by ATP-competitive ligands.
Article in Nature communications, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 41 citations in OpenAlex.
- Degradation of ACSL3 by influenza A virus shifts unfolded protein response from antiviral defense to viral evasion.Virologica Sinica · 2026Article
- Pyrazolylpyrimidinamines Decorated via Petasis Reaction as Small-Molecule Activators of the RNA-Degrading Ribonuclease IRE1α.ACS bio & med chem Au · 2026Article
- Mucin 2 and unfolded protein response reshape the mucus barrier in inflammatory bowel disease (Review).Molecular medicine reports · 2026Review
- Chemically-induced degradation of the endoplasmic-reticulum stress sensor IRE1 by a VHL-recruiting chimera.Nature communications · 2025Article
- QM/MM Free Energy Calculations of IRE1 Reveal a Unique Protonation State of the Catalytic Lys599.Journal of computational chemistry · 2025Article
- Molecular mechanisms mediated by liquid-liquid phase separation in chronic liver disease progression.iScience · 2025Review
- Pharmacologic inhibition of IRE1α-dependent decay protects alveolar epithelial identity and prevents pulmonary fibrosis in mice.The Journal of clinical investigation · 2025Article
- Harnessing indole scaffolds to identify small-molecule IRE1α inhibitors modulating XBP1 mRNA splicing.Nature communications · 2025Article
- Protein translation rate determines neocortical neuron fate.Nature communications · 2024Article
- Kaempferol attenuates particle-induced osteogenic impairment by regulating ER stress via the IRE1α-XBP1s pathway.The Journal of biological chemistry · 2024Article
- Dual RNase activity of IRE1 as a target for anticancer therapies.Journal of cell communication and signaling · 2023Review
- Targeting Ribonucleases with Small Molecules and Bifunctional Molecules.ACS chemical biology · 2023Review
- X-box Binding Protein 1: An Adaptor in the Pathogenesis of Atherosclerosis.Aging and disease · 2023Review
- TGFβ1 regulates HRas-mediated activation of IRE1α through the PERK-RPAP2 axis in keratinocytes.Molecular carcinogenesis · 2022Article
- Selective inhibitors of SARM1 targeting an allosteric cysteine in the autoregulatory ARM domain.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Pharmacological targeting of endoplasmic reticulum stress in disease.Nature reviews. Drug discovery · 2022Review
- The IRE1α pathway in glomerular diseases: The unfolded protein response and beyond.Frontiers in molecular medicine · 2022Review
- Newly synthesized mRNA escapes translational repression during the acute phase of the mammalian unfolded protein response.PloS one · 2022Article
- Decoding non-canonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1α.Nature communications · 2021Article
- Living Dangerously: Protective and Harmful ER Stress Responses in Pancreatic β-Cells.Diabetes · 2021Review
Corrections and comments
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Authors and funding
18 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Inositol-Requiring Enzyme 1 (IRE1) is an essential component of the Unfolded Protein Response. IRE1 spans the endoplasmic reticulum membrane, comprising a sensory lumenal domain, and tandem kinase and endoribonuclease (RNase) cytoplasmic domains. Excess unfolded proteins in the ER lumen induce dimerization and oligomerization of IRE1, triggering kinase trans-autophosphorylation and RNase activation. Known ATP-competitive small-molecule IRE1 kinase inhibitors either allosterically disrupt or stabilize the active dimeric unit, accordingly inhibiting or stimulating RNase activity. Previous allosteric RNase activators display poor selectivity and/or weak cellular activity. In this study, we describe a class of ATP-competitive RNase activators possessing high selectivity and strong cellular activity. This class of activators binds IRE1 in the kinase front pocket, leading to a distinct conformation of the activation loop. Our findings reveal exquisitely precise interdomain regulation within IRE1, advancing the mechanistic understanding of this important enzyme and its investigation as a potential small-molecule therapeutic target.
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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.