Hydantoin analogs inhibit the fully assembled ClpXP protease without affecting the individual peptidase and chaperone domains.
Manuscript_Hydantoin analogs ...
SI_Hydantoin analogs inhibit the ...
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
MetadataShow full item record
AbstractProteolysis mediated by ClpXP is a crucial cellular process linked to bacterial pathogenesis. The development of specific inhibitors has largely focused on ClpP. However, this focus was challenged by a recent finding showing that conformational control by ClpX leads to a rejection of ClpP binders. Thus, we here follow up on a hit molecule from a high throughput screen performed against the whole ClpXP complex and demonstrate that stable inhibition with high potency is possible. Further investigations revealed that the small molecule binds to ClpP without affecting its activity. Likewise, the molecule does not inhibit ClpX and retains the overall oligomeric state of ClpXP upon binding. Structure activity relationship studies confirmed structural constraints in all three parts of the molecule suggesting binding into a defined stereospecific pocket. Overall, the inhibition of ClpXP without affecting the individual components represents a novel mechanism with perspectives for further optimization for in situ applications.
CitationOrg Biomol Chem. 2019 Aug 14;17(30):7124-7127. doi: 10.1039/c9ob01339c. Epub 2019 Jul 17.
AffiliationHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
PublisherRoyal Society of Chemistry
The following license files are associated with this item:
- Creative Commons
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-ShareAlike 4.0 International
- A Chemical Disruptor of the ClpX Chaperone Complex Attenuates the Virulence of Multidrug-Resistant Staphylococcus aureus.
- Authors: Fetzer C, Korotkov VS, Thänert R, Lee KM, Neuenschwander M, von Kries JP, Medina E, Sieber SA
- Issue date: 2017 Dec 4
- Cryo-EM structure of the ClpXP protein degradation machinery.
- Authors: Gatsogiannis C, Balogh D, Merino F, Sieber SA, Raunser S
- Issue date: 2019 Oct
- Selective Activation of Human Caseinolytic Protease P (ClpP).
- Authors: Stahl M, Korotkov VS, Balogh D, Kick LM, Gersch M, Pahl A, Kielkowski P, Richter K, Schneider S, Sieber SA
- Issue date: 2018 Oct 26
- Reversible Inhibitors Arrest ClpP in a Defined Conformational State that Can Be Revoked by ClpX Association.
- Authors: Pahl A, Lakemeyer M, Vielberg MT, Hackl MW, Vomacka J, Korotkov VS, Stein ML, Fetzer C, Lorenz-Baath K, Richter K, Waldmann H, Groll M, Sieber SA
- Issue date: 2015 Dec 21
- Identification and Characterization of Approved Drugs and Drug-Like Compounds as Covalent <i>Escherichia coli</i> ClpP Inhibitors.
- Authors: Sassetti E, Durante Cruz C, Tammela P, Winterhalter M, Augustyns K, Gribbon P, Windshügel B
- Issue date: 2019 May 31