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Inhibitory mechanism of reveromycin A at the tRNA binding site of a class I synthetase

Author

Listed:
  • Bingyi Chen

    (Sun Yat-sen University
    Sun Yat-sen University)

  • Siting Luo

    (Sun Yat-sen University
    Sun Yat-sen University)

  • Songxuan Zhang

    (Sun Yat-sen University
    Sun Yat-sen University)

  • Yingchen Ju

    (Sun Yat-sen University
    Sun Yat-sen University)

  • Qiong Gu

    (Sun Yat-sen University)

  • Jun Xu

    (Sun Yat-sen University)

  • Xiang-Lei Yang

    (Scripps Research Institute)

  • Huihao Zhou

    (Sun Yat-sen University
    Sun Yat-sen University)

Abstract

The polyketide natural product reveromycin A (RM-A) exhibits antifungal, anticancer, anti-bone metastasis, anti-periodontitis and anti-osteoporosis activities by selectively inhibiting eukaryotic cytoplasmic isoleucyl-tRNA synthetase (IleRS). Herein, a co-crystal structure suggests that the RM-A molecule occupies the substrate tRNAIle binding site of Saccharomyces cerevisiae IleRS (ScIleRS), by partially mimicking the binding of tRNAIle. RM-A binding is facilitated by the copurified intermediate product isoleucyl-adenylate (Ile-AMP). The binding assays confirm that RM-A competes with tRNAIle while binding synergistically with l-isoleucine or intermediate analogue Ile-AMS to the aminoacylation pocket of ScIleRS. This study highlights that the vast tRNA binding site of the Rossmann-fold catalytic domain of class I aminoacyl-tRNA synthetases could be targeted by a small molecule. This finding will inform future rational drug design.

Suggested Citation

  • Bingyi Chen & Siting Luo & Songxuan Zhang & Yingchen Ju & Qiong Gu & Jun Xu & Xiang-Lei Yang & Huihao Zhou, 2021. "Inhibitory mechanism of reveromycin A at the tRNA binding site of a class I synthetase," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21902-0
    DOI: 10.1038/s41467-021-21902-0
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    Cited by:

    1. A. Brkic & M. Leibundgut & J. Jablonska & V. Zanki & Z. Car & V. Petrovic Perokovic & A. Marsavelski & N. Ban & I. Gruic-Sovulj, 2023. "Antibiotic hyper-resistance in a class I aminoacyl-tRNA synthetase with altered active site signature motif," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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