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Crystal structure of Saccharomyces cerevisiae isoleucyl-tRNA synthetase in complex with reveromycin A and isoleucine
Structural highlights
FunctionPublication Abstract from PubMedAminoacyl-tRNA synthetases (AARSs) are essential for decoding the genetic code by accurately attaching amino acids to their corresponding tRNAs, making them attractive drug targets for treating various diseases. The natural product reveromycin A (RMA) demonstrates therapeutic potential for osteoporosis and other osteoclast-related disorders by selectively inducing osteoclast apoptosis, with human cytoplasmic isoleucyl-tRNA synthetase (HcIleRS) identified as its putative functional target. In this study, recombinant HcIleRS was expressed and characterized, and RMA was demonstrated to potently inhibit HcIleRS activity with an IC(50) value of 36â¯nM measured using an ATP consumption assay. The dissociation constant (K(d)) for RMA binding to HcIleRS was measured at 429â¯nM, which improved to 90â¯nM and 28â¯nM in the presence of an intermediate analog and the substrate isoleucine (l-Ile), respectively. Two co-crystal structures of Saccharomyces cerevisiae IleRS (ScIleRS) complexed with RMA and l-Ile, resolved under the same crystallization conditions, revealed that l-Ile facilitates RMA binding to the tRNA(Ile) CCA-end binding site in the catalytic domain by increasing hydrophobic stacking interactions between RMA and active site residues. Consequently, RMA not only directly competes with tRNA(Ile) for binding to the catalytic domain but also disrupts its interactions with the editing domain by blocking necessary conformational movements. Notably, the C18 hemisuccinate chain of RMA exhibited alternative conformations in the two structures, suggesting that its interaction with the KMSKS motif is not essential for the high-affinity binding. This substrate-aided cooperative binding mechanism facilitates the potent inhibition of IleRS by RMA and offers valuable insights for developing potential combination therapies targeting AARSs. Substrate l-isoleucine facilitates the hyper inhibition of reveromycin A on human cytoplasmic isoleucyl-tRNA synthetase.,Chen B, Yi F, Qi H, Xu J, Su J, Zhou H, Liu H Arch Biochem Biophys. 2026 Mar 14;780:110789. doi: 10.1016/j.abb.2026.110789. PMID:41839287[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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