title: Small molecule binding, docking, and characterization of the interaction between Pth1 and peptidyl-tRNA.
abstract: 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.
authors.affiliation: Department of Chemistry, University of Alabama in Huntsville, 301 Sparkman Drive, Huntsville, AL 35899, USA. robert.mcfeeters@uah.edu.
authors.forename: Mary C
authors.initials: MC
authors.lastname: Hames
authors.forename: Hana
authors.initials: H
authors.lastname: McFeeters
authors.forename: W Blake
authors.initials: WB
authors.lastname: Holloway
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Stanley
authors.forename: Volker S
authors.initials: VS
authors.lastname: Urban
authors.forename: Robert L
authors.initials: RL
authors.lastname: McFeeters
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D002265:Carboxylic Ester Hydrolases / Q000737:chemistry* / Q000378:metabolism; D004926:Escherichia coli; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D062105:Molecular Docking Simulation; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000378:metabolism; D009502:Neutrons; D012346:RNA, Transfer, Amino Acyl / Q000737:chemistry / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; D008024:Ligands; D046912:Multiprotein Complexes; D012346:RNA, Transfer, Amino Acyl; D016601:RNA-Binding Proteins; D054852:Small Molecule Libraries; C019037:tRNA, peptidyl-; D002265:Carboxylic Ester Hydrolases; C019674:aminoacyl-tRNA hydrolase