7OD0

Mirolysin in complex with compound 9

This is a non-PDB format compatible entry.

Summary for 7OD0

• Entry DOI: 10.2210/pdb7od0/pdb
• Descriptor: Mirolysin, 2,1,3-benzothiadiazol-4-ylmethanamine, 1,2-ETHANEDIOL, ... (8 entities in total)
• Functional Keywords: bacterial protease, hydrolase
• Biological source: Tannerella forsythia
• Total number of polymer chains: 6
• Total formula weight: 188813.02

Authors

Zak, K.M.,Bostock, M.J.,Ksiazek, M. (deposition date: 2021-04-28, release date: 2021-08-04, Last modification date: 2024-11-13)

Primary citation

Zak, K.M.,Bostock, M.J.,Waligorska, I.,Thogersen, I.B.,Enghild, J.J.,Popowicz, G.M.,Grudnik, P.,Potempa, J.,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

PubMed Abstract: Mirolysin is a secretory protease of , 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) ) that blocks promirolysin maturation and functions as a competitive inhibitor ( = 3.2 µM), binding to the S1' subsite of the substrate-binding pocket. Cpd shows superior specificity and does not interact with other proteases or Lys/Arg-specific proteases.

PubMed: 34210221
DOI: 10.1080/14756366.2021.1937619

Experimental method

X-RAY DIFFRACTION (2.1 Å)