Tailored Peptide Phenyl Esters Block ClpXP Proteolysis by an Unusual Breakdown into a Heptamer–Hexamer Assembly
| العنوان: | Tailored Peptide Phenyl Esters Block ClpXP Proteolysis by an Unusual Breakdown into a Heptamer–Hexamer Assembly |
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| المؤلفون: | Ralf Strasser, Friederike M. Möller, Dóra Balogh, Stephan A. Sieber, Hendrik Dietz, Eva Bertosin, Markus Lakemeyer |
| المصدر: | Angewandte Chemie International Edition. 58:7127-7132 |
| بيانات النشر: | Wiley, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Staphylococcus aureus, Serine Proteinase Inhibitors, Protein Conformation, Proteolysis, Peptide, Random hexamer, 010402 general chemistry, 01 natural sciences, Catalysis, Structure-Activity Relationship, Bacterial Proteins, medicine, chemistry.chemical_classification, medicine.diagnostic_test, 010405 organic chemistry, Esters, Stereoisomerism, Endopeptidase Clp, General Chemistry, 0104 chemical sciences, Amino acid, Enzyme, Catalytic cycle, chemistry, Biophysics, Protein Multimerization, Peptides, Molecular probe |
| الوصف: | The proteolytic complex ClpXP is fundamental to bacterial homeostasis and pathogenesis. Because of its conformational flexibility, the development of potent ClpXP inhibitors is challenging, and novel tools to decipher its intricate regulation are urgently needed. Herein, we present amino acid based phenyl esters as molecular probes to study the activity and oligomerization of the ClpXP complex of S. aureus. Systematic screening of (R)- and (S)-amino acids led to compounds showing potent inhibition, as well as stimulation of ClpXP-mediated proteolysis. Substoichiometric binding of probes arrested ClpXP in an unprecedented heptamer-hexamer assembly, in which the two heptameric ClpP rings are dissociated from each other. At the same time, the affinity between ClpX and ClpP increased, leading to inhibition of both enzymes. This conformational arrest is beneficial for the consolidated shutdown of ClpXP, as well as for the study of the oligomeric state during its catalytic cycle. |
| تدمد: | 1521-3773 1433-7851 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::af229e62f058dba063e787f164f554a3 https://doi.org/10.1002/anie.201901056 |
| حقوق: | CLOSED |
| رقم الأكسشن: | edsair.doi.dedup.....af229e62f058dba063e787f164f554a3 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15213773 14337851 |
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