3UFA

Crystal structure of the staphylococcal serine protease SplA in complex with a specific phosphonate inhibitor

Summary for 3UFA

• Entry DOI: 10.2210/pdb3ufa/pdb
• Related PRD ID: PRD_000908
• Descriptor: Serine protease splA, N-(3-carboxypropanoyl)-L-valyl-N-[(1S)-2-phenyl-1-phosphonoethyl]-L-prolinamide, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: chymotrypsin like fold, serine protease, extracellular protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Staphylococcus aureus
• Cellular location: Secreted: Q2FXC2
• Total number of polymer chains: 2
• Total formula weight: 44872.28

Authors

Zdzalik, M.,Pietrusewicz, E.,Pustelny, K.,Stec-Niemczyk, J.,Popowicz, G.M.,Potempa, J.,Oleksyszyn, J.,Dubin, G. (deposition date: 2011-10-31, release date: 2013-01-23, Last modification date: 2024-10-30)

Primary citation

Burchacka, E.,Zdzalik, M.,Niemczyk, J.S.,Pustelny, K.,Popowicz, G.,Wladyka, B.,Dubin, A.,Potempa, J.,Sienczyk, M.,Dubin, G.,Oleksyszyn, J.
Development and binding characteristics of phosphonate inhibitors of SplA protease from Staphylococcus aureus.
Protein Sci., 23:179-189, 2014

PubMed 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.

PubMed: 24375505
DOI: 10.1002/pro.2403

Experimental method

X-RAY DIFFRACTION (1.8 Å)