3str | pdb_00003str

Strep Peptide Deformylase with a time dependent thiazolidine hydroxamic acid

spinqualitylabelsall models 3str, resolution 1.75Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3str is a 1 chain structure with sequence from "diplococcus_pneumoniae"_(klein_1884)_weichselbaum_1886 "diplococcus pneumoniae" (klein 1884) weichselbaum 1886. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 3LI, GOL, NI, SO4 Gene: defB, def3 ("Diplococcus pneumoniae" (Klein 1884) Weichselbaum 1886) Activity: Peptide deformylase, with EC number 3.5.1.88 Resources: FirstGlance, OCA, RCSB, PDBsum Function [Q939R9_STREE] Removes the formyl group from the N-terminal Met of newly synthesized proteins. Requires at least a dipeptide for an efficient rate of reaction. N-terminal L-methionine is a prerequisite for activity but the enzyme has broad specificity at other positions (By similarity).[HAMAP-Rule:MF_00163] Publication Abstract from PubMed 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. In order to gain a better 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 displayed 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. Understanding the Origins of Time Dependent Inhibition by Polypeptide Deformylase Inhibitors.,Totoritis R, Duraiswami C, Taylor AN, Kerrigan JJ, Campobasso N, Ward P, King BW, Murray-Thompson MF, Jones AD, Van Aller G, Aubart KM, Zalacain M, Thrall SH, Meek TD, Schwartz B Biochemistry. 2011 Jun 28. PMID:21711014 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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