ArticleScience advances2019
Mechanism of the allosteric activation of the ClpP protease machinery by substrates and active-site inhibitors.
Article in Science advances, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 60 citations in OpenAlex.
- Molecular mechanisms of mitochondrial AAA+ proteases.The Journal of biological chemistry · 2026Review
- Subunit-specific isotope labelling of heteromeric complexes using cell-free protein expression: application to the 760 kDa ClpXP molecular machine.RSC chemical biology · 2026Article
- Structural and mechanistic insights into caseinolytic protease inhibition for antimicrobial development against Pseudomonas plecoglossicida.PLoS pathogens · 2026Article
- Cryo-EM structures of human ClpXP reveal mechanisms of assembly and proteolytic activation.Nature communications · 2026Article
- Allosteric regulation of proteolytic machines unveiled by the synergy between cryo-EM and solution NMR spectroscopy.The Biochemical journal · 2025Review
- 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
- Production, Purification, and Biochemical Characterization of a Novel ATP-Dependent Caseinolytic Protease from the Marine BacteriumMicroorganisms · 2025Article
- Chemical tools to expand the ligandable proteome: Diversity-oriented synthesis-based photoreactive stereoprobes.Cell chemical biology · 2024Article
- Nonallosteric activation of posttranslational modification enzymes by active site-directed inhibitors.Computational and structural biotechnology journal · 2024Article
- Cryo-EM structures of human ClpXP reveal mechanisms of assembly and proteolytic activation.bioRxiv : the preprint server for biology · 2024Article
- Molecular insights into the dynamic modulation of bacterial ClpP function and oligomerization by peptidomimetic boronate compounds.Scientific reports · 2024Article
- Deuteration of proteins boosted by cell lysates: high-resolution amide and HMagnetic resonance (Gottingen, Germany) · 2024Article
- Small-molecule TIP60 inhibitors enhance regulatory T cell induction through TIP60-P300 acetylation crosstalk.iScience · 2023Article
- Identification of macrocyclic peptides which activate bacterial cylindrical proteases.RSC medicinal chemistry · 2023Article
- Design, Biological Evaluation, and Computer-Aided Analysis of Dihydrothiazepines as Selective Antichlamydial Agents.Journal of medicinal chemistry · 2023Article
- From Angstroms to Nanometers: Measuring Interatomic Distances by Solid-State NMR.Chemical reviews · 2022Review
- Review
- Recent structural insights into the mechanism of ClpP protease regulation by AAA+ chaperones and small molecules.The Journal of biological chemistry · 2022Review
- Armeniaspirol analogues with more potent Gram-positive antibiotic activity show enhanced inhibition of the ATP-dependent proteases ClpXP and ClpYQ.RSC medicinal chemistry · 2022Article
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Coordinated conformational transitions in oligomeric enzymatic complexes modulate function in response to substrates and play a crucial role in enzyme inhibition and activation. Caseinolytic protease (ClpP) is a tetradecameric complex, which has emerged as a drug target against multiple pathogenic bacteria. Activation of different ClpPs by inhibitors has been independently reported from drug development efforts, but no rationale for inhibitor-induced activation has been hitherto proposed. Using an integrated approach that includes x-ray crystallography, solid- and solution-state nuclear magnetic resonance, molecular dynamics simulations, and isothermal titration calorimetry, we show that the proteasome inhibitor bortezomib binds to the ClpP active-site serine, mimicking a peptide substrate, and induces a concerted allosteric activation of the complex. The bortezomib-activated conformation also exhibits a higher affinity for its cognate unfoldase ClpX. We propose a universal allosteric mechanism, where substrate binding to a single subunit locks ClpP into an active conformation optimized for chaperone association and protein processive degradation.
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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.