Hydantoin analogs inhibit the fully assembled ClpXP protease without affecting the individual peptidase and chaperone domains.
Manuscript_Hydantoin analogs ...
SI_Hydantoin analogs inhibit the ...
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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
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- Tailored Peptide Phenyl Esters Block ClpXP Proteolysis by an Unusual Breakdown into a Heptamer-Hexamer Assembly.
- Authors: Lakemeyer M, Bertosin E, Möller F, Balogh D, Strasser R, Dietz H, Sieber SA
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- Cryo-EM structure of the ClpXP protein degradation machinery.
- Authors: Gatsogiannis C, Balogh D, Merino F, Sieber SA, Raunser S
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- Enzymatic and structural similarities between the Escherichia coli ATP-dependent proteases, ClpXP and ClpAP.
- Authors: Grimaud R, Kessel M, Beuron F, Steven AC, Maurizi MR
- Issue date: 1998 May 15
- The ClpXP protease is dispensable for degradation of unfolded proteins in Staphylococcus aureus.
- Authors: Stahlhut SG, Alqarzaee AA, Jensen C, Fisker NS, Pereira AR, Pinho MG, Thomas VC, Frees D
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