Structural Basis for Specific Inhibition of tRNA Synthetase by an ATP Competitive Inhibitor
Article, Other literature type
- Publisher: Elsevier BV
Chemistry & Biology,
Molecular Biology | Drug Discovery | Biochemistry | Pharmacology | Molecular Medicine | Clinical Biochemistry | Article
Pharmaceutical inhibitors of aminoacyl-tRNA synthetases demand high species and family specificity. The antimalarial ATP-mimetic cladosporin selectively inhibits P. falciparum LysRS (PfLysRS). How the binding to a universal ATP site achieves the specificity is unknown. Here we report 3 crystal structures of cladosporin with human LysRS, PfLysRS, and a Pf-like human LysRS mutant. In all 3 structures, cladosporin occupies the class defining ATP-binding pocket, replacing the adenosine portion of ATP. Three residues holding the methyltetrahydro-pyran moiety of cladosporin are critical for cladosporin's specificity against LysRS over other class II tRNA synthetase families. The species-exclusive inhibition of PfLysRS is linked to a structural divergence beyond the active site that mounts a lysine-specific stabilizing response to binding cladosporin. These analyses reveal that inherent divergence of tRNA synthetase structural assembly may allow for highly specific inhibition even through the otherwise universal substrate binding pocket and highlight the potential for structure driven drug development.