9V9F
Methionyl-tRNA synthetase from Staphylococcus aureus in complex with an inhibitor
This is a non-PDB format compatible entry.
Summary for 9V9F
| Entry DOI | 10.2210/pdb9v9f/pdb |
| Descriptor | Methionine--tRNA ligase, 9-[(1R)-1-[[3,5-bis(chloranyl)phenyl]amino]ethyl]-N-(2-hydroxyethyl)-N-methyl-2-morpholin-4-yl-4-oxidanylidene-pyrido[1,2-a]pyrimidine-7-carboxamide, 1,2-ETHANEDIOL, ... (4 entities in total) |
| Functional Keywords | methionyl-trna synthetase, complex, ligase |
| Biological source | Staphylococcus aureus |
| Total number of polymer chains | 1 |
| Total formula weight | 61872.65 |
| Authors | |
| Primary citation | Su, J.,Qiao, A.,Huang, W.,Xu, J.,Lu, F.,Zhang, H.,Deng, Q.,Zou, J.,Wang, Z.,Lei, J.,Zhou, H. Discovery of a triple-site inhibitor targeting bacterial methionyl-tRNA synthetase through combined drug repurposing screening and generative AI-assisted optimization. Nucleic Acids Res., 54:-, 2026 Cited by PubMed Abstract: Methionyl-tRNA synthetase (MetRS) plays an critical role in protein translation by catalyzing the attachment of l-methionine (l-Met) to its cognate tRNAMet and has long been recognized as a valuable target for antimicrobial drug development. In this study, a drug repurposing screen of a kinase inhibitor library identified AZD8186, a clinically investigated PI3Kβ modulator, as a promising inhibitor of Staphylococcus aureus MetRS (SaMetRS). The binding mode of AZD8186 to SaMetRS was elucidated through co-crystallography, and subsequent knowledge-directed ligand optimization resulted in enhanced inhibitory activity and improved synthetic accessibility. Furthermore, we developed a novel conservation-aware and interaction-guided 3D generative AI model, designated DiffDeCIG, to facilitate structure-based drug design. DiffDeCIG modified inhibitors to establish additional interactions preferentially with conserved residues within the active pocket of SaMetRS. The optimal compound, MRS-9, potentially competed with all three substrates of MetRS (ATP, l-Met and tRNAMet), and demonstrated over a 300-fold increase in inhibitory activity relative to AZD8186. Importantly, MRS-9 selectively inhibited type 1 MetRS enzymes, while minimally affecting the tested type 2 MetRSs, including the human MetRS, thereby reducing potential adverse effects. This study reveals a novel triple-site inhibitory mechanism targeting MetRS and highlights an integrated strategy that combines knowledge-directed and AI-guided approaches in drug design. PubMed: 42152681DOI: 10.1093/nar/gkag488 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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