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Zak, K.M. ; Bostock, M.J. ; Waligorska, I.* ; Thøgersen, I.B.* ; Enghild, J.J.* ; Popowicz, G.M. ; Grudnik, P.* ; Potempa, J.S.* ; Ksiazek, M.*

Latency, thermal stability, and identification of an inhibitory compound of mirolysin, a secretory protease of the human periodontopathogen Tannerella forsythia.

J. Enzyme Inhib. Med. Chem. 36, 1267-1281 (2021)

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Mirolysin is a secretory protease of Tannerella forsythia, a member of the dysbiotic oral microbiota responsible for periodontitis. In this study, we show that mirolysin latency is achieved by a "cysteine-switch" mechanism exerted by Cys23 in the N-terminal profragment. Mutation of Cys23 shortened the time needed for activation of the zymogen from several days to 5 min. The mutation also decreased the thermal stability and autoproteolysis resistance of promirolysin. Mature mirolysin is a thermophilic enzyme and shows optimal activity at 65 °C. Through NMR-based fragment screening, we identified a small molecule (compound (cpd) 9) that blocks promirolysin maturation and functions as a competitive inhibitor (K_i = 3.2 µM), binding to the S1' subsite of the substrate-binding pocket. Cpd 9 shows superior specificity and does not interact with other T. forsythia proteases or Lys/Arg-specific proteases.

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Publication type Article: Journal article

Document type Scientific Article

Keywords Nmr-based Fragment Screening ; Periodontitis ; Tannerella Forsythia ; Protease Inhibitors ; Proteolysis; Porphyromonas-gingivalis; Periodontal Health; Virulence Factors; Nmr-spectroscopy; Red Complex; Suppression; Gingipains; Mechanism; Prevalence; Activation

ISSN (print) / ISBN 1475-6366

e-ISSN 1475-6374

Journal Journal of Enzyme Inhibition and Medicinal Chemistry

Quellenangaben Volume: 36, Issue: 1, Pages: 1267-1281

Publisher Informa Healthcare

Publishing Place London

Reviewing status Peer reviewed

Institute(s) Institute of Structural Biology (STB)

Grants PLGrid Infrastructure
Foundation for Polish Science
Helmholtz Zentrum Munchen
Polish Ministry of Science and Higher Education
National Science Center, Poland