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The Mechanism of Caseinolytic Protease (ClpP) Inhibition

Authors

  • Malte Gersch,

    1. Center for Integrated Protein Science Munich (CIPSM), Technische Universität München, Department of Chemistry, Institute of Advanced Studies (IAS), Lichtenbergstrasse 4, 85747 Garching (Germany)
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  • Felix Gut,

    1. Institute of Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032 Marburg (Germany)
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    • These authors contributed equally to this work.

  • Dr. Vadim S. Korotkov,

    1. Center for Integrated Protein Science Munich (CIPSM), Technische Universität München, Department of Chemistry, Institute of Advanced Studies (IAS), Lichtenbergstrasse 4, 85747 Garching (Germany)
    2. Aviru Exist, Lichtenbergstrasse 4, 85747 Garching (Germany)
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    • These authors contributed equally to this work.

  • Johannes Lehmann,

    1. Center for Integrated Protein Science Munich (CIPSM), Technische Universität München, Department of Chemistry, Institute of Advanced Studies (IAS), Lichtenbergstrasse 4, 85747 Garching (Germany)
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  • Dr. Thomas Böttcher,

    1. Aviru Exist, Lichtenbergstrasse 4, 85747 Garching (Germany)
    2. Harvard Medical School, Department of Biological Chemistry and Molecular Pharmacology, 240 Longwood Ave., Boston, MA 02115 (USA)
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  • Dr. Marion Rusch,

    1. Max Planck-Institut für Molekulare Physiologie, Abteilung Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
    2. Technische Universität Dortmund, Fakultät Chemie, Lehrbereich Chemische Biologie, Otto-Hahn-Strasse 6, 44227 Dortmund (Germany)
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  • Dr. Christian Hedberg,

    1. Max Planck-Institut für Molekulare Physiologie, Abteilung Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
    2. Technische Universität Dortmund, Fakultät Chemie, Lehrbereich Chemische Biologie, Otto-Hahn-Strasse 6, 44227 Dortmund (Germany)
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  • Prof. Dr. Herbert Waldmann,

    1. Max Planck-Institut für Molekulare Physiologie, Abteilung Chemische Biologie, Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
    2. Technische Universität Dortmund, Fakultät Chemie, Lehrbereich Chemische Biologie, Otto-Hahn-Strasse 6, 44227 Dortmund (Germany)
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  • Prof. Dr. Gerhard Klebe,

    1. Institute of Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032 Marburg (Germany)
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  • Prof. Dr. Stephan A. Sieber

    Corresponding author
    1. Center for Integrated Protein Science Munich (CIPSM), Technische Universität München, Department of Chemistry, Institute of Advanced Studies (IAS), Lichtenbergstrasse 4, 85747 Garching (Germany)
    2. Aviru Exist, Lichtenbergstrasse 4, 85747 Garching (Germany)
    • Center for Integrated Protein Science Munich (CIPSM), Technische Universität München, Department of Chemistry, Institute of Advanced Studies (IAS), Lichtenbergstrasse 4, 85747 Garching (Germany)
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  • We acknowledge funding from the Deutsche Forschungsgemeinschaft, FOR1409, SFB749, SFB1035, CIPSM, and the European Research Council (ERC Grant no. 268309 and ERC Starting Grant no. 259024). We thank Martina Müller, Matthias Stahl, Mona Wolff, Jenny Sachweh, Daniela Bauer, and Jan Vomacka for help with experiments, Arne Schröder and Marco Balabajew for assistance with docking experiments, and Matthew Nodwell for critical evaluation of the manuscript. M.G. and F.G. wish to express their thanks to the Heidelberg Life-Science Lab for providing a scientifically inspiring environment.

Abstract

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Catch me if you can: The ClpP protease mediates protein homeostasis and can be efficiently inhibited by β-lactones. A combination of molecular docking, mutagenesis, activity-based protein profiling, and kinetics studies now reveals the mechanism of ClpP inhibition. A hydrophobic pocket next to the active site allows binding of long aliphatic and aromatic residues. The preferred stereoisomer binds into the oxyanion hole.

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