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Two-site recognition of Staphylococcus aureus peptidoglycan by lysostaphin SH3b

DOI: 10.1038/s41589-019-0393-4 DOI Help

Authors: Luz S. Gonzalez-delgado (University of Sheffield) , Hannah Walters-morgan (University of Birmingham) , Bartłomiej Salamaga (University of Sheffield) , Angus J. Robertson (University of Sheffield) , Andrea M. Hounslow (University of Sheffield) , Elżbieta Jagielska (International Institute of Molecular and Cell Biology, Poland) , Izabela Sabala (International Institute of Molecular and Cell Biology, Poland) , Mike P. Williamson (University of Sheffield) , Andrew Lovering (University of Birmingham) , Stéphane Mesnage (University of Sheffield)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Chemical Biology , VOL 51

State: Published (Approved)
Published: November 2019
Diamond Proposal Number(s): 19880

Abstract: Lysostaphin is a bacteriolytic enzyme targeting peptidoglycan, the essential component of the bacterial cell envelope. It displays a very potent and specific activity toward staphylococci, including methicillin-resistant Staphylococcus aureus. Lysostaphin causes rapid cell lysis and disrupts biofilms, and is therefore a therapeutic agent of choice to eradicate staphylococcal infections. The C-terminal SH3b domain of lysostaphin recognizes peptidoglycans containing a pentaglycine crossbridge and has been proposed to drive the preferential digestion of staphylococcal cell walls. Here we elucidate the molecular mechanism underpinning recognition of staphylococcal peptidoglycan by the lysostaphin SH3b domain. We show that the pentaglycine crossbridge and the peptide stem are recognized by two independent binding sites located on opposite sides of the SH3b domain, thereby inducing a clustering of SH3b domains. We propose that this unusual binding mechanism allows synergistic and structurally dynamic recognition of S. aureus peptidoglycan and underpins the potent bacteriolytic activity of this enzyme.

Journal Keywords: Bacteria; Membrane lipids; NMR spectroscopy; X-ray crystallography

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography

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