ArticleThe Journal of biological chemistry2016
Structure and Functional Properties of the Active Form of the Proteolytic Complex, ClpP1P2, from Mycobacterium tuberculosis.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 66 citations in OpenAlex.
- Repurposing approved drugs as potential inhibitors of Mycobacterium tuberculosis ClpP: Structure-based virtual screening, molecular dynamics, and in vitro evaluation.Molecular diversity · 2026Article
- Mode of action guided metagenomic natural product discovery reveals convergent evolution of a ClpP-targeting motif.Nature communications · 2026Article
- 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
- Structure of the central Staphylococcus aureus AAA+ protease MecA/ClpC/ClpP.Communications biology · 2025Article
- The ClpA chaperone and the two adaptor proteins modulate the fate of the model substrate tagged with a SsrA-degron of Leptospira.The Biochemical journal · 2025Article
- Allosteric regulation of proteolytic machines unveiled by the synergy between cryo-EM and solution NMR spectroscopy.The Biochemical journal · 2025Review
- Structural Insights into Bortezomib-Induced Activation of the Caseinolytic Chaperone-Protease System in Mycobacterium tuberculosis.Nature communications · 2025Article
- TamGen: drug design with target-aware molecule generation through a chemical language model.Nature communications · 2024Article
- Targeted protein degradation in mycobacteria uncovers antibacterial effects and potentiates antibiotic efficacy.Nature communications · 2024Article
- Electrostatic interactions guide substrate recognition of the prokaryotic ubiquitin-like protein ligase PafA.Nature communications · 2023Article
- 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
- Identification of the inhibitory mechanism of ecumicin and rufomycin 4-7 on the proteolytic activity of Mycobacterium tuberculosis ClpC1/ClpP1/ClpP2 complex.Tuberculosis (Edinburgh, Scotland) · 2023Article
- Identification of Arginine Phosphorylation in Mycolicibacterium smegmatis.Microbiology spectrum · 2022Article
- Acyldepsipeptide Analogues: A Future Generation Antibiotics for Tuberculosis Treatment.Pharmaceutics · 2022Review
- Article
- Structural insights into ClpP protease side exit pore-opening by a pH drop coupled with substrate hydrolysis.The EMBO journal · 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
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Authors and funding
7 authors at 4 institutions in 1 country.
Funding
Abstract
The ClpP protease complex and its regulatory ATPases, ClpC1 and ClpX, inMycobacterium tuberculosis(Mtb) are essential and, therefore, promising drug targets. TheMtbClpP protease consists of two heptameric rings, one composed of ClpP1 and the other of ClpP2 subunits. Formation of the enzymatically active ClpP1P2 complex requires binding of N-blocked dipeptide activators. We have found a new potent activator, benzoyl-leucine-leucine (Bz-LL), that binds with higher affinity and promotes 3-4-fold higher peptidase activity than previous activators. Bz-LL-activated ClpP1P2 specifically stimulates the ATPase activity ofMtbClpC1 and ClpX. The ClpC1P1P2 and ClpXP1P2 complexes exhibit 2-3-fold enhanced ATPase activity, peptide cleavage, and ATP-dependent protein degradation. The crystal structure of ClpP1P2 with bound Bz-LL was determined at a resolution of 3.07 Å and with benzyloxycarbonyl-Leu-Leu (Z-LL) bound at 2.9 Å. Bz-LL was present in all 14 active sites, whereas Z-LL density was not resolved. Surprisingly, Bz-LL adopts opposite orientations in ClpP1 and ClpP2. In ClpP1, Bz-LL binds with the C-terminal leucine side chain in the S1 pocket. One C-terminal oxygen is close to the catalytic serine, whereas the other contacts backbone amides in the oxyanion hole. In ClpP2, Bz-LL binds with the benzoyl group in the S1 pocket, and the peptide hydrogen bonded between parallel β-strands. The ClpP2 axial loops are extended, forming an open axial channel as has been observed with bound ADEP antibiotics. Thus occupancy of the active sites of ClpP allosterically alters sites on the surfaces thereby affecting the association of ClpP1 and ClpP2 rings, interactions with regulatory ATPases, and entry of protein substrates.
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