Inhibitory mechanism of reveromycin A at the tRNA binding site of a class I synthetase.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 33712620.
- Also identified by DOI 10.1038/s41467-021-21902-0 and PMC identifier 7955072.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 tRNA<sup>Ile</sup> binding site of Saccharomyces cerevisiae IleRS (ScIleRS), by partially mimicking the binding of tRNA<sup>Ile</sup>. RM-A binding is facilitated by the copurified intermediate product isoleucyl-adenylate (Ile-AMP). The binding assays confirm that RM-A competes with tRNA<sup>Ile</sup> 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.
Medical subject headings
- Binding Sites
- Ligases
- Pyrans
- RNA, Transfer
- Spiro Compounds