ArticleThe Journal of biological chemistry2015
Cleavage Specificity of Mycobacterium tuberculosis ClpP1P2 Protease and Identification of Novel Peptide Substrates and Boronate Inhibitors with Anti-bacterial Activity.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed.
- Proteostasis-targeted antibacterial strategies.Journal of microbiology (Seoul, Korea) · 2026Review
- Highly specific Immunoproteasome inhibitor M3258 induces proteotoxic stress and apoptosis in KMT2A::AFF1 driven acute lymphoblastic leukemia.Scientific reports · 2025Article
- Article
- Identification of new ClpC1-NTD binders for Mycobacterium tuberculosis drug development.Scientific reports · 2025Article
- TamGen: drug design with target-aware molecule generation through a chemical language model.Nature communications · 2024Article
- Protein degradation by a component of the chaperonin-linked protease ClpP.Genes to cells : devoted to molecular & cellular mechanisms · 2024Review
- A role for the S4-domain containing protein YlmH in ribosome-associated quality control in Bacillus subtilis.Nucleic acids research · 2024Article
- Review
- Identification of Arginine Phosphorylation in Mycolicibacterium smegmatis.Microbiology spectrum · 2022Article
- Catalytic Properties of Caseinolytic Protease Subunit ofMolecules (Basel, Switzerland) · 2022Article
- The essentialScience advances · 2022Article
- Cellular functions of the ClpP protease impacting bacterial virulence.Frontiers in molecular biosciences · 2022Review
- Advances in Key Drug Target Identification and New Drug Development for Tuberculosis.BioMed research international · 2022Review
- Probing allosteric interactions in homo-oligomeric molecular machines using solution NMR spectroscopy.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Recent developments in the medicinal chemistry of single boron atom-containing compounds.Acta pharmaceutica Sinica. B · 2021Review
- ClpX Is Essential and Activated by Single-Strand DNA Binding Protein in Mycobacteria.Journal of bacteriology · 2021Article
- Control of Toxin-Antitoxin Systems by Proteases inFrontiers in molecular biosciences · 2021Review
- Mitochondrial ClpP serine protease-biological function and emerging target for cancer therapy.Cell death & disease · 2020Review
- Article
- An allosteric switch regulatesProceedings of the National Academy of Sciences of the United States of America · 2020Article
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Authors and funding
13 authors.
Funding
Abstract
The ClpP1P2 protease complex is essential for viability in Mycobacteria tuberculosis and is an attractive drug target. Using a fluorogenic tripeptide library (Ac-X3X2X1-aminomethylcoumarin) and by determining specificity constants (kcat/Km), we show that ClpP1P2 prefers Met ≫ Leu > Phe > Ala in the X1 position, basic residues or Trp in the X2 position, and Pro ≫ Ala > Trp in the X3 position. We identified peptide substrates that are hydrolyzed up to 1000 times faster than the standard ClpP substrate. These positional preferences were consistent with cleavage sites in the protein GFPssrA by ClpXP1P2. Studies of ClpP1P2 with inactive ClpP1 or ClpP2 indicated that ClpP1 was responsible for nearly all the peptidase activity, whereas both ClpP1 and ClpP2 contributed to protein degradation. Substrate-based peptide boronates were synthesized that inhibit ClpP1P2 peptidase activity in the submicromolar range. Some of them inhibited the growth of Mtb cells in the low micromolar range indicating that cleavage specificity of Mtb ClpP1P2 can be used to design novel anti-bacterial agents.
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