ArticleProceedings of the National Academy of Sciences of the United States of America2014
Crystal structure of Mycobacterium tuberculosis ClpP1P2 suggests a model for peptidase activation by AAA+ partner binding and substrate delivery.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 95 citations in OpenAlex.
- Targeting ClpP Protease: Emerging Therapeutic Strategies and Small-Molecule Modulators in Drug Discovery.Medicinal research reviews · 2026Review
- ClpC1-dependent iron homeostasis underlies mycobacterial defense against oxygen-driven Fenton reaction during reactivation.Microbiology spectrum · 2026Article
- Repurposing approved drugs as potential inhibitors of Mycobacterium tuberculosis ClpP: Structure-based virtual screening, molecular dynamics, and in vitro evaluation.Molecular diversity · 2026Article
- Fred Goldberg machines in the pathogenesis of Mycobacterium tuberculosis.The Journal of biological chemistry · 2026Review
- Structural and mechanistic insights into caseinolytic protease inhibition for antimicrobial development against Pseudomonas plecoglossicida.PLoS pathogens · 2026Article
- ClpC1-targeting peptide natural products differentially dysregulate the proteome of Mycobacterium tuberculosis.Nature communications · 2026Article
- Structural Insights into Bortezomib-Induced Activation of the Caseinolytic Chaperone-Protease System in Mycobacterium tuberculosis.Nature communications · 2025Article
- Molecular insights into the dynamic modulation of bacterial ClpP function and oligomerization by peptidomimetic boronate compounds.Scientific reports · 2024Article
- Targeting bacterial degradation machinery as an antibacterial strategy.The Biochemical journal · 2023Review
- Interactome Analysis Identifies MSMEI_3879 as a Substrate of Mycolicibacterium smegmatis ClpC1.Microbiology spectrum · 2023Article
- Acyldepsipeptide Antibiotics and a Bioactive Fragment Thereof Differentially PerturbACS chemical biology · 2023Article
- Antibiotic Acyldepsipeptides Stimulate themBio · 2022Article
- Identification of Arginine Phosphorylation in Mycolicibacterium smegmatis.Microbiology spectrum · 2022Article
- Acyldepsipeptide Analogues: A Future Generation Antibiotics for Tuberculosis Treatment.Pharmaceutics · 2022Review
- ESKAPE Pathogens: Looking at Clp ATPases as Potential Drug Targets.Antibiotics (Basel, Switzerland) · 2022Review
- The essentialScience advances · 2022Article
- Recent structural insights into the mechanism of ClpP protease regulation by AAA+ chaperones and small molecules.The Journal of biological chemistry · 2022Review
- Structure and function of ClpXP, a AAA+ proteolytic machine powered by probabilistic ATP hydrolysis.Critical reviews in biochemistry and molecular biology · 2022Review
- Structural determinants of regulated proteolysis in pathogenic bacteria by ClpP and the proteasome.Current opinion in structural biology · 2021Review
- Ribosome hibernation: a new molecular framework for targeting nonreplicating persisters of mycobacteria.Microbiology (Reading, England) · 2021Review
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Caseinolytic peptidase P (ClpP), a double-ring peptidase with 14 subunits, collaborates with ATPases associated with diverse activities (AAA+) partners to execute ATP-dependent protein degradation. Although many ClpP enzymes self-assemble into catalytically active homo-tetradecamers able to cleave small peptides, the Mycobacterium tuberculosis enzyme consists of discrete ClpP1 and ClpP2 heptamers that require a AAA+ partner and protein-substrate delivery or a peptide agonist to stabilize assembly of the active tetradecamer. Here, we show that cyclic acyldepsipeptides (ADEPs) and agonist peptides synergistically activate ClpP1P2 by mimicking AAA+ partners and substrates, respectively, and determine the structure of the activated complex. Our studies establish the basis of heteromeric ClpP1P2 assembly and function, reveal tight coupling between the conformations of each ring, show that ADEPs bind only to one ring but appear to open the axial pores of both rings, provide a foundation for rational drug development, and suggest strategies for studying the roles of individual ClpP1 and ClpP2 rings in Clp-family proteolysis.
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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.