Selectivity profiling of DegP substrates and inhibitors |
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Authors: | Patrick Hauske Michael Meltzer Christian Ottmann Tobias Krojer Tim Clausen Michael Ehrmann Markus Kaiser |
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Institution: | 1. Chemical Genomics Centre der Max-Planck-Gesellschaft, Otto-Hahn-Str. 15, D-44227 Dortmund, Germany;2. Zentrum für Medizinische Biotechnologie, FB Biologie und Geographie, Universität Duisburg-Essen, D-45117 Essen, Germany;3. Research Institute for Molecular Pathology (IMP), Dr. Bohrgasse 7, A-1030 Vienna, Austria;4. Cardiff School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3US, United Kingdom |
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Abstract: | Protein quality control factors are involved in many key physiological processes and severe human diseases that are based on misfolding or amyloid formation. Prokaryotic representatives are often virulence factors of pathogenic bacteria. Therefore, protein quality control factors represent a novel class of drug targets. The bacterial serine protease DegP, belonging to the widely conserved family of HtrA proteases, exhibits unusual structural and functional plasticity that could be exploited by small molecule modulators. However, only one weak synthetic peptide substrate and no inhibitors are available to date. We report the identification of a potent heptameric pNA-substrate and chloromethyl ketone based inhibitors of DegP. In addition, specificity profiling resulted in the identification of one strong inhibitor and a potent substrate for subtilisin as well as a number of specific elastase substrates and inhibitors. |
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