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

Author

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  • Shaileja Chopra

    (The University of North Carolina at Chapel Hill)

  • Andrés Palencia

    (European Molecular Biology Laboratory, Grenoble Outstation and Unit of Virus Host-Cell Interactions, UJF-EMBL-CNRS, UMI 3265, 6 rue Jules Horowitz, BP181, 38042 Grenoble Cedex 9, France)

  • Cornelia Virus

    (The University of North Carolina at Chapel Hill)

  • Ashutosh Tripathy

    (UNC Macromolecular Interactions Facility, The University of North Carolina at Chapel Hill)

  • Brenda R. Temple

    (R. L. Juliano Structural Bioinformatics Core Facility, The University of North Carolina at Chapel Hill)

  • Adrian Velazquez-Campoy

    (Institute of Biocomputation and Physics of Complex Systems (BIFI), Universidad de Zaragoza)

  • Stephen Cusack

    (European Molecular Biology Laboratory, Grenoble Outstation and Unit of Virus Host-Cell Interactions, UJF-EMBL-CNRS, UMI 3265, 6 rue Jules Horowitz, BP181, 38042 Grenoble Cedex 9, France)

  • John S. Reader

    (The University of North Carolina at Chapel Hill)

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 tRNALeu 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.

Suggested Citation

  • Shaileja Chopra & Andrés Palencia & Cornelia Virus & Ashutosh Tripathy & Brenda R. Temple & Adrian Velazquez-Campoy & Stephen Cusack & John S. Reader, 2013. "Plant tumour biocontrol agent employs a tRNA-dependent mechanism to inhibit leucyl-tRNA synthetase," Nature Communications, Nature, vol. 4(1), pages 1-9, June.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms2421
    DOI: 10.1038/ncomms2421
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