Plant tumour biocontrol agent employs a tRNA-dependent mechanism to inhibit leucyl-tRNA synthetase

Nat Commun. 2013;4:1417. doi: 10.1038/ncomms2421.

Abstract

Leucyl-tRNA synthetases (LeuRSs) have an essential role in translation and are promising targets for antibiotic development. Agrocin 84 is a LeuRS inhibitor produced by the biocontrol agent Agrobacterium radiobacter K84 that targets pathogenic strains of A. tumefaciens, the causative agent of plant tumours. Agrocin 84 acts as a molecular Trojan horse and is processed inside the pathogen into a toxic moiety (TM84). Here we show using crystal structure, thermodynamic and kinetic analyses, that this natural antibiotic employs a unique and previously undescribed mechanism to inhibit LeuRS. TM84 requires tRNA(Leu) for tight binding to the LeuRS synthetic active site, unlike any previously reported inhibitors. TM84 traps the enzyme-tRNA complex in a novel 'aminoacylation-like' conformation, forming novel interactions with the KMSKS loop and the tRNA 3'-end. Our findings reveal an intriguing tRNA-dependent inhibition mechanism that may confer a distinct evolutionary advantage in vivo and inform future rational antibiotic design.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine Nucleotides / chemistry
  • Adenine Nucleotides / pharmacology*
  • Agrobacterium tumefaciens / drug effects
  • Agrobacterium tumefaciens / enzymology*
  • Aminoacylation / drug effects
  • Biological Control Agents*
  • Calorimetry
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Leucine-tRNA Ligase / antagonists & inhibitors*
  • Leucine-tRNA Ligase / chemistry
  • Leucine-tRNA Ligase / metabolism
  • Models, Molecular
  • Plant Tumors / microbiology*
  • Protein Binding / drug effects
  • Protein Conformation
  • Protein Structure, Tertiary
  • RNA, Plant / chemistry
  • RNA, Plant / metabolism*
  • RNA, Transfer / chemistry
  • RNA, Transfer / metabolism*

Substances

  • Adenine Nucleotides
  • Biological Control Agents
  • Enzyme Inhibitors
  • RNA, Plant
  • agrocin 84
  • RNA, Transfer
  • Leucine-tRNA Ligase

Associated data

  • PDB/3ZGZ