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

• Published in: Nature communications 2021-03, Vol.12 (1), p.1616-1616, Article 1616
• Main Authors: Chen, Bingyi, Luo, Siting, Zhang, Songxuan, Ju, Yingchen, Gu, Qiong, Xu, Jun, Yang, Xiang-Lei, Zhou, Huihao
• Format: Article
• Language: English
• Subjects: 42/70; 631/337/574/1793; 631/45/535/1266; 631/45/607; 631/92/609; 82/80; 82/83; Amino Acyl-tRNA Synthetases - chemistry; Amino Acyl-tRNA Synthetases - drug effects; Aminoacylation; Binding sites; Binding Sites - drug effects; Biomedical materials; Crystal structure; Drug development; Fungi; Fungicides; Humanities and Social Sciences; Isoleucine; Isoleucine-tRNA ligase; Isoleucine-tRNA Ligase - chemistry; Isoleucine-tRNA Ligase - drug effects; L-isoleucine; Ligands; Ligases - chemistry; Ligases - drug effects; Metastases; Mimicry; Models, Molecular; Molecular structure; multidisciplinary; Natural products; Osteoporosis; Osteoporosis - drug therapy; Periodontitis; Pyrans - antagonists & inhibitors; RNA, Transfer - chemistry; RNA, Transfer - drug effects; Saccharomyces cerevisiae; Science; Science (multidisciplinary); Spiro Compounds - antagonists & inhibitors; Substrates; tRNA; Yeast
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-21902-0

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 tRNA Ile binding site of Saccharomyces cerevisiae IleRS ( Sc IleRS), by partially mimicking the binding of tRNA Ile . RM-A binding is facilitated by the copurified intermediate product isoleucyl-adenylate (Ile-AMP). The binding assays confirm that RM-A competes with tRNA Ile while binding synergistically with l -isoleucine or intermediate analogue Ile-AMS to the aminoacylation pocket of Sc IleRS. 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. Reveromycin A (RM-A) selectively inhibits eukaryotic cytoplasmic isoleucyltRNA synthetase (IleRS). Herein, the authors show that RM-A molecule occupies the tRNA Ile binding site of Saccharomyces cerevisiae IleRS, and that RM-A cooperates with isoleucine or isoleucyl-adenylate for IleRS binding.