PuSH - Publication Server of Helmholtz Zentrum München

Export: TXT Text RIS Endnote (RIS) BIB BibTeX
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)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
Impact Factor
Scopus SNIP
Scopus
Cited By
Altmetric
5.051
1.517
2
Tags
Annotations
Special Publikation
Hide on homepage

Edit extra information
Edit own tags
Private
Edit own annotation
Private
Hide on publication lists
on hompage
Mark as special
publikation
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
Language english
Publication Year 2021
HGF-reported in Year 2021
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 Article Number: , Supplement: ,
Publisher Informa Healthcare
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Structural Biology (STB)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Enabling and Novel Technologies
PSP Element(s) G-503000-001
Grants PLGrid Infrastructure
Foundation for Polish Science
Helmholtz Zentrum Munchen
Polish Ministry of Science and Higher Education
National Science Center, Poland
DOI 10.1080/14756366.2021.1937619
WOS ID WOS:000669103700001
Scopus ID 85109161933
PubMed ID 34210221
Erfassungsdatum 2021-07-27
[➜Report correction]