2. Academic Validation
  3. Inhibitory mechanism of reveromycin A at the tRNA binding site of a class I synthetase

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

  • Nat Commun. 2021 Mar 12;12(1):1616. doi: 10.1038/s41467-021-21902-0.
Bingyi Chen 1 2,  Siting Luo 1 2,  Songxuan Zhang 1 2,  Yingchen Ju 1 2,  Qiong Gu 2,  Jun Xu 2,  Xiang-Lei Yang 3,  Huihao Zhou 4 5
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
  • 2 Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
  • 3 Department of Molecular Medicine, Scripps Research Institute, La Jolla, CA, 92037, USA.
  • 4 Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China. [email protected].
  • 5 Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China. [email protected].
PMID: 33712620 DOI: 10.1038/s41467-021-21902-0
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.

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