Premium
Reversible Inhibitors Arrest ClpP in a Defined Conformational State that Can Be Revoked by ClpX Association
Author(s) -
Pahl Axel,
Lakemeyer Markus,
Vielberg MarieTheres,
Hackl Mathias W.,
Vomacka Jan,
Korotkov Vadim S.,
Stein Martin L.,
Fetzer Christian,
LorenzBaath Katrin,
Richter Klaus,
Waldmann Herbert,
Groll Michael,
Sieber Stephan A.
Publication year - 2015
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201507266
Subject(s) - proteolysis , chemistry , protease , chaperone (clinical) , small molecule , biochemistry , enzyme , biophysics , microbiology and biotechnology , biology , medicine , pathology
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.