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Latency, thermal stability, and identification of an inhibitory compound of mirolysin, a secretory protease of the human periodontopathogen Tannerella forsythia.
Zak, Krzysztof M; Bostock, Mark J; Waligorska, Irena; Thøgersen, Ida B; Enghild, Jan J; Popowicz, Grzegorz M; Grudnik, Przemyslaw; Potempa, Jan; Ksiazek, Miroslaw.
Afiliación
  • Zak KM; Helmholtz Zentrum München, Institute of Structural Biology, Neuherberg, Germany.
  • Bostock MJ; Malopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland.
  • Waligorska I; Helmholtz Zentrum München, Institute of Structural Biology, Neuherberg, Germany.
  • Thøgersen IB; Biomolecular NMR and Center for Integrated Protein Science Munich at Department Chemie, Technical University of Munich, Garching, Germany.
  • Enghild JJ; Department of Microbiology, Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, Krakow, Poland.
  • Popowicz GM; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
  • Grudnik P; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
  • Potempa J; Helmholtz Zentrum München, Institute of Structural Biology, Neuherberg, Germany.
  • Ksiazek M; Biomolecular NMR and Center for Integrated Protein Science Munich at Department Chemie, Technical University of Munich, Garching, Germany.
J Enzyme Inhib Med Chem ; 36(1): 1267-1281, 2021 Dec.
Article en En | MEDLINE | ID: mdl-34210221
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 (Ki = 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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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Péptido Hidrolasas / Periodontitis / Inhibidores de Proteasas / Tannerella forsythia Tipo de estudio: Diagnostic_studies Límite: Humans Idioma: En Revista: J Enzyme Inhib Med Chem Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2021 Tipo del documento: Article País de afiliación: Alemania

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Péptido Hidrolasas / Periodontitis / Inhibidores de Proteasas / Tannerella forsythia Tipo de estudio: Diagnostic_studies Límite: Humans Idioma: En Revista: J Enzyme Inhib Med Chem Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2021 Tipo del documento: Article País de afiliación: Alemania