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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.

Original publication

DOI

10.1038/ncomms2421

Type

Journal article

Journal

Nat Commun

Publication Date

2013

Volume

4

Keywords

Adenine Nucleotides, Agrobacterium tumefaciens, Aminoacylation, Biological Control Agents, Calorimetry, Crystallography, X-Ray, Enzyme Inhibitors, Leucine-tRNA Ligase, Models, Molecular, Plant Tumors, Protein Binding, Protein Conformation, Protein Structure, Tertiary, RNA, Plant, RNA, Transfer