ArticleACS chemical biology2016
Structural and Functional Analysis of the Allosteric Inhibition of IRE1α with ATP-Competitive Ligands.
Article in ACS chemical biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
What it found
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Who cites it
50 citing papers in PubMed, 85 citations in OpenAlex.
- QM/MM Free Energy Calculations of IRE1 Reveal a Unique Protonation State of the Catalytic Lys599.Journal of computational chemistry · 2025Article
- 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
- Advances in pyrazolo[1,5-RSC advances · 2025Review
- Endoplasmic reticulum stress in diseases.MedComm · 2024Review
- 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
- Article
- Endoplasmic reticulum stress and unfolded protein accumulation correlate to seizure recurrence in focal cortical dysplasia patients.Cell stress & chaperones · 2022Article
- TMBIM6 promotes diabetic tubular epithelial cell survival and albumin endocytosis by inhibiting the endoplasmic reticulum stress sensor, IRE1α.Molecular biology reports · 2022Article
- The epithelial-specific ER stress sensor ERN2/IRE1β enables host-microbiota crosstalk to affect colon goblet cell development.The Journal of clinical investigation · 2022Article
- ER Stress is Involved in Mast Cells Degranulation via IRE1α/miR-125/Lyn Pathway in an Experimental Intracerebral Hemorrhage Mouse Model.Neurochemical research · 2022Article
- Kinases on Double Duty: A Review of UniProtKB Annotated Bifunctionality within the Kinome.Biomolecules · 2022Review
- Pharmacological targeting of endoplasmic reticulum stress in disease.Nature reviews. Drug discovery · 2022Review
- Towards Understanding the Relationship Between ER Stress and Unfolded Protein Response in Amyotrophic Lateral Sclerosis.Frontiers in aging neuroscience · 2022Review
- Structure-Based Drug Discovery of IRE1 Modulators.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Endoplasmic Reticulum Stress and the Unfolded Protein Response in Cerebral Ischemia/Reperfusion Injury.Frontiers in cellular neuroscience · 2022Review
- The role and therapeutic implication of endoplasmic reticulum stress in inflammatory cancer transformation.American journal of cancer research · 2022Review
- ATP-competitive partial antagonists of the IRE1α RNase segregate outputs of the UPR.Nature chemical biology · 2021Article
- Evolution and function of the epithelial cell-specific ER stress sensor IRE1β.Mucosal immunology · 2021Review
Corrections and comments
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Authors and funding
13 authors at 4 institutions in 1 country.
Funding
Abstract
The accumulation of unfolded proteins under endoplasmic reticulum (ER) stress leads to the activation of the multidomain protein sensor IRE1α as part of the unfolded protein response (UPR). Clustering of IRE1α lumenal domains in the presence of unfolded proteins promotes kinase trans-autophosphorylation in the cytosol and subsequent RNase domain activation. Interestingly, there is an allosteric relationship between the kinase and RNase domains of IRE1α, which allows ATP-competitive inhibitors to modulate the activity of the RNase domain. Here, we use kinase inhibitors to study how ATP-binding site conformation affects the activity of the RNase domain of IRE1α. We find that diverse ATP-competitive inhibitors of IRE1α promote dimerization and activation of RNase activity despite blocking kinase autophosphorylation. In contrast, a subset of ATP-competitive ligands, which we call KIRAs, allosterically inactivate the RNase domain through the kinase domain by stabilizing monomeric IRE1α. Further insight into how ATP-competitive inhibitors are able to divergently modulate the RNase domain through the kinase domain was gained by obtaining the first structure of apo human IRE1α in the RNase active back-to-back dimer conformation. Comparison of this structure with other existing structures of IRE1α and integration of our extensive structure activity relationship (SAR) data has led us to formulate a model to rationalize how ATP-binding site ligands are able to control the IRE1α oligomeric state and subsequent RNase domain activity.
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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.