These authors contributed equally to this work.
The Mechanism of Caseinolytic Protease (ClpP) Inhibition†
Article first published online: 30 JAN 2013
Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Angewandte Chemie International Edition
Volume 52, Issue 10, pages 3009–3014, March 4, 2013
How to Cite
Gersch, M., Gut, F., Korotkov, V. S., Lehmann, J., Böttcher, T., Rusch, M., Hedberg, C., Waldmann, H., Klebe, G. and Sieber, S. A. (2013), The Mechanism of Caseinolytic Protease (ClpP) Inhibition . Angew. Chem. Int. Ed., 52: 3009–3014. doi: 10.1002/anie.201204690
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.
- Issue published online: 27 FEB 2013
- Article first published online: 30 JAN 2013
- Manuscript Revised: 29 OCT 2012
- Manuscript Received: 15 JUN 2012
- Deutsche Forschungsgemeinschaft
- European Research Council. Grant Numbers: 268309, 259024
- enzyme inhibitors;
- molecular docking;
- structure–activity relationship
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.