9vci | pdb_00009vci

Crystal structure of Escherichia coli tryptophanyl-tRNA synthetase in complex with an inhibitor

spinqualitylabelsall models 9vci, resolution 1.88Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9vci is a 2 chain structure with sequence from Escherichia coli. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.88Å Ligands: A1ERR, CLW, SO4, TYM Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function E2QFN4_ECOLX Catalyzes the attachment of tryptophan to tRNA(Trp).[HAMAP-Rule:MF_00140] Publication Abstract from PubMed The escalating threat of antibiotic resistance poses a critical challenge to global public health, necessitating the urgent development of novel therapeutic agents with distinct mechanisms of action and unique structural scaffolds. Tryptophanyl-tRNA synthetase (TrpRS) has emerged as a promising antibacterial target. Our previous study demonstrated that the clinically utilized Bruton's tyrosine kinase (BTK) inhibitor tirabrutinib, along with several of its analogues, can simultaneously occupy both the substrates l-Trp and tRNA(Trp) A76 binding sites of Escherichia coli tryptophanyl-tRNA synthetase (EcTrpRS), thereby effectively inhibiting its catalytic activity. Building on this finding, we employed structure-based drug design to systematically optimize the interactions of tirabrutinib analogues with the l-Trp and tRNA(Trp) binding sites, as well as to further extend the structure to the adjacent ATP binding site within the catalytic pocket of EcTrpRS to establish additional interactions, leading to the design and synthesis of 22 new derivatives. Among these, WRS22 (a racemic mixture) demonstrated the best binding to EcTrpRS, with a DeltaT(m) value of 33.2 degrees C and 90 % inhibition rate at 10 muM concentration. Its binding affinity for EcTrpRS (K(d) = 0.33 +/- 0.03 muM) is superior to that of the positive control, indolmycin (K(d) = 0.71 +/- 0.1 muM). Notably, WRS22 displayed no affinity to human cytoplasmic TrpRS (HcTrpRS) and its interaction with human BTK is likely to be disrupted, indicating high degree of target selectivity. Therefore, the structure-guided design successfully developed new tirabrutinib analogues as inhibitors of bacterial TrpRS, presenting a promising lead compound for the development of AARS-based antibacterial agents. Structure-based design of tirabrutinib derivatives as inhibitors of bacterial tryptophanyl-tRNA synthetase.,Xia K, Peng X, Xiao L, Huang Q, Xu J, Chen B, Zhou H Bioorg Chem. 2025 Sep 9;165:108978. doi: 10.1016/j.bioorg.2025.108978. PMID:40945024 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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