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Structural determinants of inhibition of Porphyromonas gingivalis gingipain K by KYT-36, a potent, selective, and bioavailable peptidase inhibitor

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cris.lastimport.scopus2024-02-12T20:29:33Z
dc.abstract.enPorphyromonas gingivalis is a member of the dysbiotic oral microbiome and a “keystone pathogen” that causes severe periodontal disease, which is among the most prevalent infectious diseases. Part of the virulence factors secreted by P. gingivalis are the essential cysteine peptidases gingipain K (Kgp) and R (RgpA and RgpB), which account for 85% of the extracellular proteolytic activity of the pathogen and are thus prime targets for inhibition. We report the high-resolution (1.20 Å) complex structure of Kgp with KYT-36, a peptide-derived, potent, bioavailable and highly selective inhibitor, which is widely used for studies in vitro, in cells and in vivo. Sub-nanomolar inhibition of Kgp is achieved by tight binding to the active-site cleft, which is covered for its sub-sites S3 through S1’ under establishment of nine hydrophobic interactions, 14 hydrogen bonds and one salt bridge. In addition, an inhibitor carbonyl carbon that mimics the scissile carbonyl of substrates is pyramidalized and just 2.02 Å away from the catalytic nucleophile of Kgp, C477Sγ. Thus, the crystal structure emulates a reaction intermediate of the first nucleophilic attack during catalysis of cysteine peptidases. The present study sets the pace for the development of tailored next-generation drugs to tackle P. gingivalis.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorŁasica, Anna
dc.contributor.authorGuevara, Tibisay
dc.contributor.authorRodríguez-Banqueri, Arturo
dc.contributor.authorPotempa, Jan
dc.contributor.authorGomis-Rüth, F. Xavier
dc.contributor.authorPotempa, Barbara
dc.contributor.authorKsiążek, Mirosław
dc.date.accessioned2024-01-26T08:21:25Z
dc.date.available2024-01-26T08:21:25Z
dc.date.copyright2019-03-20
dc.date.issued2019
dc.description.accesstimeAT_PUBLICATION
dc.description.financeNie dotyczy
dc.description.number1
dc.description.versionFINAL_PUBLISHED
dc.description.volume9
dc.identifier.doi10.1038/S41598-019-41354-3
dc.identifier.issn2045-2322
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/120886
dc.identifier.weblinkhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426963/pdf/41598_2019_Article_41354.pdf
dc.languageeng
dc.pbn.affiliationbiological sciences
dc.relation.ispartofScientific Reports
dc.relation.pages1-8
dc.rightsCC-BY
dc.sciencecloudnosend
dc.titleStructural determinants of inhibition of Porphyromonas gingivalis gingipain K by KYT-36, a potent, selective, and bioavailable peptidase inhibitor
dc.typeJournalArticle
dspace.entity.typePublication