Small molecule binding, docking, and characterization of the interaction between Pth1 and peptidyl-tRNA

Int J Mol Sci. 2013 Nov 19;14(11):22741-52. doi: 10.3390/ijms141122741.


Bacterial Pth1 is essential for viability. Pth1 cleaves the ester bond between the peptide and nucleotide of peptidyl-tRNA generated from aborted translation, expression of mini-genes, and short ORFs. We have determined the shape of the Pth1:peptidyl-tRNA complex using small angle neutron scattering. Binding of piperonylpiperazine, a small molecule constituent of a combinatorial synthetic library common to most compounds with inhibitory activity, was mapped to Pth1 via NMR spectroscopy. We also report computational docking results, modeling piperonylpiperazine binding based on chemical shift perturbation mapping. Overall these studies promote Pth1 as a novel antibiotic target, contribute to understanding how Pth1 interacts with its substrate, advance the current model for cleavage, and demonstrate feasibility of small molecule inhibition.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Carboxylic Ester Hydrolases / chemistry*
  • Carboxylic Ester Hydrolases / metabolism
  • Escherichia coli
  • Escherichia coli Proteins / chemistry*
  • Escherichia coli Proteins / genetics
  • Escherichia coli Proteins / metabolism*
  • Gene Expression Regulation, Bacterial
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Molecular Docking Simulation
  • Multiprotein Complexes / chemistry*
  • Multiprotein Complexes / metabolism
  • Neutrons
  • RNA, Transfer, Amino Acyl / chemistry
  • RNA, Transfer, Amino Acyl / metabolism*
  • RNA-Binding Proteins / chemistry
  • RNA-Binding Proteins / metabolism
  • Small Molecule Libraries / chemistry*


  • Anti-Bacterial Agents
  • Escherichia coli Proteins
  • Ligands
  • Multiprotein Complexes
  • RNA, Transfer, Amino Acyl
  • RNA-Binding Proteins
  • Small Molecule Libraries
  • tRNA, peptidyl-
  • Carboxylic Ester Hydrolases
  • aminoacyl-tRNA hydrolase