Abstract
Staphylococcus simulans biovar staphylolyticus lysostaphin efficiently cleaves Staphylococcus aureus cell walls. The protein is in late clinical trials as a topical anti-staphylococcal agent, and can be used to prevent staphylococcal growth on artificial surfaces. Moreover, the gene has been both stably engineered into and virally delivered to mice or livestock to obtain resistance against staphylococci. Here, we report the first crystal structure of mature lysostaphin and two structures of its isolated catalytic domain at 3.5, 1.78 and 1.26 Å resolution, respectively. The structure of the mature active enzyme confirms its expected organization into catalytic and cell-wall-targeting domains. It also indicates that the domains are mobile with respect to each other because of the presence of a highly flexible peptide linker. The high-resolution structures of the catalytic domain provide details of Zn2+ coordination and may serve as a starting point for the engineering of lysostaphin variants with improved biotechnological characteristics.Structured digital abstractlysostaphin by x-ray crystallography (1,2).
Highlights
Staphylococcus aureus is a common human and animal pathogen of major clinical significance [1]
Staphylococcus simulans lysostaphin (EC 3.4.24.75) has staphylolytic properties that were originally discovered in the 1960s [2,3] and immediately attracted interest as a means of combating staphylococcal infection [4]
Apart from direct application in humans, lysostaphin has been considered for the eradication of S. aureus biofilms from artificial surfaces [14] and as an antimicrobial agent in catheter coatings [15]
Summary
Staphylococcus aureus is a common human and animal pathogen of major clinical significance [1]. The crystal structure shows the expected overall organization of lysostaphin into an N-terminal catalytic domain and a C-terminal CWT domain (Fig. 3). The domains of the four molecules in the asymmetric unit of the mature lysostaphin crystals overlap very well, which may in part reflect the use of noncrystallographic symmetry restraints necessary at this resolution.
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