Structural and Functional Insights into Lysostaphin-Substrate Interaction
Tossavainen, H., Raulinaitis, V., Kauppinen, L., Pentikäinen, U., Maaheimo, H., & Permi, P. (2018). Structural and Functional Insights into Lysostaphin-Substrate Interaction. Frontiers in Molecular Biosciences, 5, Article 60. https://doi.org/10.3389/fmolb.2018.00060
Julkaistu sarjassa
Frontiers in Molecular BiosciencesTekijät
Päivämäärä
2018Tekijänoikeudet
© 2018 Tossavainen, Raulinaitis, Kauppinen, Pentikäinen, Maaheimo and Permi
Lysostaphin from Staphylococcus simulans and its family enzymes rapidly acquire
prominence as the next generation agents in treatment of S. aureus infections. The
specificity of lysostaphin is promoted by its C-terminal cell wall targeting domain
selectivity toward pentaglycine bridges in S. aureus cell wall. Scission of these cross-links
is carried out by its N-terminal catalytic domain, a zinc-dependent endopeptidase.
Understanding the determinants affecting the efficiency of catalysis and strength and
specificity of interactions lies at the heart of all lysostaphin family enzyme applications.
To this end, we have used NMR, SAXS and molecular dynamics simulations to
characterize lysostaphin structure and dynamics, to address the inter-domain interaction,
the enzyme-substrate interaction as well as the catalytic properties of pentaglycine
cleavage in solution. Our NMR structure confirms the recent crystal structure, yet,
together with the molecular dynamics simulations, emphasizes the dynamic nature of
the loops embracing the catalytic site. We found no evidence for inter-domain interaction,
but, interestingly, the SAXS data delineate two preferred conformation subpopulations.
Catalytic H329 and H360 were observed to bind a second zinc ion, which reduces
lysostaphin pentaglycine cleaving activity. Binding of pentaglycine or its lysine derivatives
to the targeting domain was found to be of very low affinity. The pentaglycine interaction
site was located to the N-terminal groove of the domain. Notably, the targeting domain
binds the peptidoglycan stem peptide Ala-D-γ-Glu-Lys-D-Ala-D-Ala with a much higher,
micromolar affinity. Binding site mapping reveals two interaction sites of different affinities
on the surface of the domain for this peptide.
...
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