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dc.contributor.authorFetzer, Christian
dc.contributor.authorKorotkov, Vadim S
dc.contributor.authorSieber, Stephan A
dc.date.accessioned2019-09-20T09:44:12Z
dc.date.available2019-09-20T09:44:12Z
dc.date.issued2019-08-14
dc.identifier.citationOrg Biomol Chem. 2019 Aug 14;17(30):7124-7127. doi: 10.1039/c9ob01339c. Epub 2019 Jul 17.en_US
dc.identifier.issn1477-0539
dc.identifier.pmid31313793
dc.identifier.doi10.1039/c9ob01339c
dc.identifier.urihttp://hdl.handle.net/10033/621954
dc.description.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.en_US
dc.language.isoenen_US
dc.publisherRoyal Society of Chemistryen_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleHydantoin analogs inhibit the fully assembled ClpXP protease without affecting the individual peptidase and chaperone domains.en_US
dc.typeArticleen_US
dc.contributor.departmentHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.en_US
dc.identifier.journalOrganic and Biomolecular Chemistryen_US
dc.source.journaltitleOrganic & biomolecular chemistry


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