20XT
Crystal structure of human ThrRS complexing with obafluorin derived inhibitor OB-D4
This is a non-PDB format compatible entry.
Summary for 20XT
| Entry DOI | 10.2210/pdb20xt/pdb |
| Descriptor | Threonine--tRNA ligase 1, cytoplasmic, ZINC ION, (2~{S},3~{R})-2-[[2,3-bis(oxidanyl)phenyl]carbonylamino]-4-(4-methoxyphenyl)-3-oxidanyl-butanoic acid (3 entities in total) |
| Functional Keywords | inhibitor, complex, covalent-inhibitor, ligase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 97663.56 |
| Authors | |
| Primary citation | Wang, Z.,Zhang, Z.,Xia, M.,Fang, M.,Xu, H.,Qiao, H.,Ding, W.,Huang, J.,Li, G.,Luo, K.,Liu, W.,Wang, J.,Yu, B.,Fang, P. Leveraging Protein Dynamics for Selective Inhibition of Threonyl-tRNA Synthetase by Obafluorin Analogs. Angew.Chem.Int.Ed.Engl., :e5509036-e5509036, 2026 Cited by PubMed Abstract: The widespread emergence of antibiotic resistance necessitates the development of novel agents with unique mechanisms of action. Obafluorin (OB), a natural β-lactone antibiotic, is a covalent inhibitor of threonyl-tRNA synthetase (ThrRS), but the high conservation of the active site between prokaryote and eukaryote ThrRSs results in minimal selectivity, hindering the therapeutic potential of OB. Here, we report a structure dynamics-based design strategy that transforms OB into a selective antibacterial agent. OB inhibits human and bacterial ThrRSs with nearly equal potency due to identical binding modes. The nitrophenyl moiety of OB is proposed as a 'kinetic sensor' that discriminates between sensitive and resistant ThrRS paralogs. Guided by this insight, we designed a series of OB analogs through rational modification of this moiety. Among them, OB-D4 bearing a para-methoxyphenyl group in place of the nitrophenyl group, exhibited a 241-fold selectivity for bacterial over human ThrRS, along with a markedly improved safety profile with minimal cytotoxicity. In a murine skin infection model, OB-D4 effectively eradicated pathogens, resolving inflammation, and promoting wound healing. Together, this work establishes a 'kinetic sensor' strategy for achieving species selectivity, turning a fundamental challenge in drug discovery-high active-site conservation-into an exploitable opportunity based on dynamic differences. PubMed: 42677972DOI: 10.1002/anie.5509036 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.5 Å) |
Structure validation
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