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

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...

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Bibliographic Details
Published in:International journal of molecular sciences 2013-11, Vol.14 (11), p.22741-22752
Main Authors: Hames, Mary C, McFeeters, Hana, Holloway, W Blake, Stanley, Christopher B, Urban, Volker S, McFeeters, Robert L
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
Carboxylic Ester Hydrolases - chemistry
Carboxylic Ester Hydrolases - metabolism
Crystal structure
docking
E coli
enzyme-substrate complex
Enzymes
Escherichia coli
Escherichia coli Proteins - chemistry
Escherichia coli Proteins - genetics
Escherichia coli Proteins - metabolism
Gene Expression Regulation, Bacterial
inhibition
Ligands
Magnetic Resonance Spectroscopy
Molecular Docking Simulation
Multiprotein Complexes - chemistry
Multiprotein Complexes - metabolism
Neutrons
Peptides
peptidyl-tRNA hydrolase
RNA, Transfer, Amino Acyl - chemistry
RNA, Transfer, Amino Acyl - metabolism
RNA-Binding Proteins - chemistry
RNA-Binding Proteins - metabolism
small angle neutron scattering
Small Molecule Libraries - chemistry
Transfer RNA
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Summary: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.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms141122741