Reversible Inhibitors Arrest ClpP in a Defined Conformational State that Can Be Revoked by ClpX Association

Axel Pahl, Markus Lakemeyer, Marie Theres Vielberg, Mathias W. Hackl, Jan Vomacka, Vadim S. Korotkov, Martin L. Stein, Christian Fetzer, Katrin Lorenz-Baath, Klaus Richter, Herbert Waldmann, Michael Groll, Stephan A. Sieber

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


Caseinolytic protease P (ClpP) is an important regulator of Staphylococcus aureus pathogenesis. A high-throughput screening for inhibitors of ClpP peptidase activity led to the identification of the first non-covalent binder for this enzyme class. Co-crystallization of the small molecule with S. aureus ClpP revealed a novel binding mode: Because of the rotation of the conserved residue proline 125, ClpP is locked in a defined conformational state, which results in distortion of the catalytic triad and inhibition of the peptidase activity. Based on these structural insights, the molecule was optimized by rational design and virtual screening, resulting in derivatives exceeding the potency of previous ClpP inhibitors. Strikingly, the conformational lock is overturned by binding of ClpX, an associated chaperone that enables proteolysis by substrate unfolding in the ClpXP complex. Thus, regulation of inhibitor binding by associated chaperones is an unexpected mechanism important for ClpP drug development.

Original languageEnglish
Pages (from-to)15892-15896
Number of pages5
JournalAngewandte Chemie International Edition in English
Issue number52
StatePublished - 21 Dec 2015


  • caseinolytic protease
  • conformational selection
  • non-covalent inhibition
  • protein crystallography
  • structural rearrangement


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