3STR

Strep Peptide Deformylase with a time dependent thiazolidine hydroxamic acid

Summary for 3STR

• Entry DOI: 10.2210/pdb3str/pdb
• Descriptor: Peptide deformylase 3, NICKEL (II) ION, SULFATE ION, ... (6 entities in total)
• Functional Keywords: alpha-beta fold, hydrolase activity, peptide deformylase activity, metal ion binding, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Streptococcus pneumoniae
• Total number of polymer chains: 1
• Total formula weight: 23897.23

Authors

Campobasso, N.,Ward, P. (deposition date: 2011-07-11, release date: 2011-07-27, Last modification date: 2024-02-28)

Primary citation

Totoritis, R.,Duraiswami, C.,Taylor, A.N.,Kerrigan, J.J.,Campobasso, N.,Smith, K.J.,Ward, P.,King, B.W.,Murrayz-Thompson, M.,Jones, A.D.,Van Aller, G.S.,Aubart, K.M.,Zalacain, M.,Thrall, S.H.,Meek, T.D.,Schwartz, B.
Understanding the origins of time-dependent inhibition by polypeptide deformylase inhibitors.
Biochemistry, 50:6642-6654, 2011

PubMed Abstract: The continual bacterial adaptation to antibiotics creates an ongoing medical need for the development of novel therapeutics. Polypeptide deformylase (PDF) is a highly conserved bacterial enzyme, which is essential for viability. It has previously been shown that PDF inhibitors represent a promising new area for the development of antimicrobial agents, and that many of the best PDF inhibitors demonstrate slow, time-dependent binding. To improve our understanding of the mechanistic origin of this time-dependent inhibition, we examined in detail the kinetics of PDF catalysis and inhibition by several different PDF inhibitors. Varying pH and solvent isotope led to clear changes in time-dependent inhibition parameters, as did inclusion of NaCl, which binds to the active site metal of PDF. Quantitative analysis of these results demonstrated that the observed time dependence arises from slow binding of the inhibitors to the active site metal. However, we also found several metal binding inhibitors that exhibited rapid, non-time-dependent onset of inhibition. By a combination of structural and chemical modification studies, we show that metal binding is only slow when the rest of the inhibitor makes optimal hydrogen bonds within the subsites of PDF. Both of these interactions between the inhibitor and enzyme were found to be necessary to observe time-dependent inhibition, as elimination of either leads to its loss.

PubMed: 21711014
DOI: 10.1021/bi200655g

Experimental method

X-RAY DIFFRACTION (1.75 Å)