L-lysyl-tRNA synthetase and ribosomal A site (LysRS/A-site)

L-lysyl-tRNA synthetase (LysRS) and the ribosomal A site are two distinct but functionally interconnected components of the protein translation machinery that serve as therapeutic targets. L-lysyl-tRNA synthetase is a class II aminoacyl-tRNA synthetase responsible for charging tRNA-Lys with its cognate amino acid, a process essential for protein synthesis and also exploited by HIV-1 for viral genome priming. The ribosomal A site, located within the small ribosomal subunit, is the decoding center where aminoacyl-tRNAs are selected based on mRNA codons. Aminoglycoside antibiotics, such as gentamicin and paromomycin, primarily target the 16S rRNA at the A site to induce translational misreading and inhibit bacterial growth, but they have also been shown to inhibit the enzymatic activity of LysRS. This dual interaction is significant in the context of treating bacterial infections and exploring nonsense mutation suppression therapies, where the interaction between the ribosome and specific tRNAs is modulated to bypass premature stop codons. Additionally, LysRS has been implicated in non-canonical roles such as cancer metastasis and immune signaling, making it a target of interest beyond traditional antimicrobial applications. The combination of these targets highlights the complexity of translation-targeted drug development and the potential for multi-target strategies to overcome resistance.

Other names

Lysyl-tRNA synthetaseKARSKRSKARS116S rRNA A-siteRibosomal decoding siteAminoacyl-tRNA synthetase and ribosome

Inhibition of aminoacyl-tRNA synthetase activity and disruption of ribosomal decoding/translocation.