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Development and binding characteristics of phosphonate inhibitors of SplA protease from Staphylococcus aureus.
- Source :
-
Protein science : a publication of the Protein Society [Protein Sci] 2014 Feb; Vol. 23 (2), pp. 179-89. Date of Electronic Publication: 2013 Dec 24. - Publication Year :
- 2014
-
Abstract
- Staphylococcus aureus is responsible for a variety of human infections, including life-threatening, systemic conditions. Secreted proteome, including a range of proteases, constitutes the major virulence factor of the bacterium. However, the functions of individual enzymes, in particular SplA protease, remain poorly characterized. Here, we report development of specific inhibitors of SplA protease. The design, synthesis, and activity of a series of α-aminoalkylphosphonate diaryl esters and their peptidyl derivatives are described. Potent inhibitors of SplA are reported, which may facilitate future investigation of physiological function of the protease. The binding modes of the high-affinity compounds Cbz-Phe(P) -(OC6 H4 -4-SO2 CH3 )2 and Suc-Val-Pro-Phe(P) -(OC6 H5 )2 are revealed by high-resolution crystal structures of complexes with the protease. Surprisingly, the binding mode of both compounds deviates from previously characterized canonical interaction of α-aminoalkylphosphonate peptidyl derivatives and family S1 serine proteases.<br /> (© 2013 The Protein Society.)
- Subjects :
- Crystallography, X-Ray
Humans
Kinetics
Organophosphonates chemistry
Protein Binding drug effects
Serine Proteinase Inhibitors chemistry
Staphylococcus aureus pathogenicity
Bacterial Proteins chemistry
Organophosphonates pharmacology
Serine Proteases chemistry
Serine Proteinase Inhibitors pharmacology
Staphylococcus aureus enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 1469-896X
- Volume :
- 23
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Protein science : a publication of the Protein Society
- Publication Type :
- Academic Journal
- Accession number :
- 24375505
- Full Text :
- https://doi.org/10.1002/pro.2403