Structural and Functional Insights Into Lysostaphin-Substrate Interaction

Frontiers in Molecular Biosciences
Helena TossavainenPerttu Permi

Abstract

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 se...Continue Reading

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Citations

Nov 7, 2019·Nature Chemical Biology·Luz S Gonzalez-DelgadoStéphane Mesnage
Sep 29, 2020·Critical Reviews in Microbiology·Alexander V GrishinVladimir G Lunin
Apr 14, 2019·Scientific Reports·Paweł MitkowskiIzabela Sabała
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Dec 23, 2020·Antibiotics·Alexander V GrishinVladimir G Lunin
May 2, 2021·International Journal of Biological Macromolecules·Emilia BonarBenedykt Wladyka

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Methods Mentioned

BETA
X-ray
NMR
gel filtration
chemical shift

Software Mentioned

xcrvfit
AMBER
CYANA
ClustalW
SHAKE
VMD
CPPTRAJ
LEaP
Sparky
NMRPipe

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