ArticleProceedings of the National Academy of Sciences of the United States of America2020
Activation by substoichiometric inhibition.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Therapeutic safety implications of SARM1 active site inhibitors: subinhibitory concentrations cause neurodegeneration.npj drug discovery · 2025Article
- Combatting virulent gut bacteria by inhibiting the biosynthesis of a two-component lanthipeptide toxin.Nature communications · 2025Article
- Molecular Tweezers Block the Functional Pore of a Protein Machine.Journal of the American Chemical Society · 2025Article
- Mechanism of allosteric activation in human mitochondrial ClpP protease.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Structural Insights into Bortezomib-Induced Activation of the Caseinolytic Chaperone-Protease System in Mycobacterium tuberculosis.Nature communications · 2025Article
- Nonallosteric activation of posttranslational modification enzymes by active site-directed inhibitors.Computational and structural biotechnology journal · 2024Article
- Rational correction of pathogenic conformational defects in HTRA1.Nature communications · 2024Article
- Heritable epigenetic changes are constrained by the dynamics of regulatory architectures.eLife · 2024Article
- A model for stimulation of enzyme activity by a competitive inhibitor based on the interaction of terazosin and phosphoglycerate kinase 1.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- HtrAs are essential for the survival of the haloarchaeonApplied and environmental microbiology · 2024Article
- Small-molecule TIP60 inhibitors enhance regulatory T cell induction through TIP60-P300 acetylation crosstalk.iScience · 2023Article
- Activation of the integrated stress response by inhibitors of its kinases.Nature communications · 2023Article
- Purification and Characterization of a DegP-Type Protease from the Marine BacteriumMicroorganisms · 2023Article
- A Single Residue within the MCR-1 Protein Confers Anticipatory Resilience.Microbiology spectrum · 2023Article
- It's ok to be outnumbered - sub-stoichiometric modulation of homomeric protein complexes.RSC medicinal chemistry · 2023Review
- Allosteric inhibition of HTRA1 activity by a conformational lock mechanism to treat age-related macular degeneration.Nature communications · 2022Article
- Substoichiometric action of long noncoding RNAs.Nature cell biology · 2022Review
- An allosteric HTRA1-calpain 2 complex with restricted activation profile.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Computational Design of Novel Allosteric Inhibitors forMolecules (Basel, Switzerland) · 2021Article
Corrections and comments
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Authors and funding
9 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Startling reports described the paradoxical triggering of the human mitogen-activated protein kinase pathway when a small-molecule inhibitor specifically inactivates the BRAF V600E protein kinase but not wt-BRAF. We performed a conceptual analysis of the general phenomenon "activation by inhibition" using bacterial and human HtrA proteases as models. Our data suggest a clear explanation that is based on the classic biochemical principles of allostery and cooperativity. Although substoichiometric occupancy of inhibitor binding sites results in partial inhibition, this effect is overrun by a concomitant activation of unliganded binding sites. Therefore, when an inhibitor of a cooperative enzyme does not reach saturating levels, a common scenario during drug administration, it may cause the contrary of the desired effect. The implications for drug development are discussed.
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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.