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dc.contributor.authorTossavainen, Helena
dc.contributor.authorRaulinaitis, Vytas
dc.contributor.authorKauppinen, Linda
dc.contributor.authorPentikäinen, Ulla
dc.contributor.authorMaaheimo, Hannu
dc.contributor.authorPermi, Perttu
dc.date.accessioned2018-07-10T05:27:25Z
dc.date.available2018-07-10T05:27:25Z
dc.date.issued2018
dc.identifier.citationTossavainen, H., Raulinaitis, V., Kauppinen, L., Pentikäinen, U., Maaheimo, H., & Permi, P. (2018). Structural and Functional Insights into Lysostaphin-Substrate Interaction. <i>Frontiers in Molecular Biosciences</i>, <i>5</i>, Article 60. <a href="https://doi.org/10.3389/fmolb.2018.00060" target="_blank">https://doi.org/10.3389/fmolb.2018.00060</a>
dc.identifier.otherCONVID_28133952
dc.identifier.urihttps://jyx.jyu.fi/handle/123456789/58883
dc.description.abstractLysostaphin 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.fi
dc.format.mimetypeapplication/pdf
dc.language.isoeng
dc.publisherFrontiers Research Foundation
dc.relation.ispartofseriesFrontiers in Molecular Biosciences
dc.rightsCC BY 4.0
dc.subject.otherlysostaphin
dc.subject.otherNMR structure
dc.subject.otherpentaglycine
dc.subject.otherpeptidoglycan
dc.subject.otherprotein dynamics
dc.subject.otherSH3b domain
dc.subject.otherstaphylococcus aureus
dc.subject.othersubstrate binding
dc.titleStructural and Functional Insights into Lysostaphin-Substrate Interaction
dc.typeresearch article
dc.identifier.urnURN:NBN:fi:jyu-201807043473
dc.contributor.laitosBio- ja ympäristötieteiden laitosfi
dc.contributor.laitosKemian laitosfi
dc.contributor.laitosDepartment of Biological and Environmental Scienceen
dc.contributor.laitosDepartment of Chemistryen
dc.contributor.oppiaineSolu- ja molekyylibiologiafi
dc.contributor.oppiaineNanoscience Centerfi
dc.contributor.oppiaineCell and Molecular Biologyen
dc.contributor.oppiaineNanoscience Centeren
dc.type.urihttp://purl.org/eprint/type/JournalArticle
dc.date.updated2018-07-04T09:15:17Z
dc.type.coarhttp://purl.org/coar/resource_type/c_2df8fbb1
dc.description.reviewstatuspeerReviewed
dc.format.pagerange60
dc.relation.issn2296-889X
dc.relation.numberinseries0
dc.relation.volume5
dc.type.versionpublishedVersion
dc.rights.copyright© 2018 Tossavainen, Raulinaitis, Kauppinen, Pentikäinen, Maaheimo and Permi
dc.rights.accesslevelopenAccessfi
dc.type.publicationarticle
dc.subject.ysoentsyymit
dc.subject.ysoantimikrobiset yhdisteet
dc.subject.ysoNMR-spektroskopia
dc.subject.ysomolekyylidynamiikka
dc.format.contentfulltext
jyx.subject.urihttp://www.yso.fi/onto/yso/p4769
jyx.subject.urihttp://www.yso.fi/onto/yso/p21949
jyx.subject.urihttp://www.yso.fi/onto/yso/p26254
jyx.subject.urihttp://www.yso.fi/onto/yso/p29332
dc.rights.urlhttps://creativecommons.org/licenses/by/4.0/
dc.relation.doi10.3389/fmolb.2018.00060
dc.type.okmA1


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