8h98

Crystal structure of chemically modified E. coli ThrS catalytic domain 1

spinqualitylabelsall models 8h98, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8h98 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 2.5Å Ligands: X5V, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function SYT_ECOLI ThrS is also a translational repressor protein, it controls the translation of its own gene by binding to its mRNA.[HAMAP-Rule:MF_00184] Publication Abstract from PubMed Aminoacyl-tRNA synthetases (AARSs), a family of essential protein synthesis enzymes, are attractive targets for drug development. Although several different types of AARS inhibitors have been identified, AARS covalent inhibitors have not been reported. Here we present five unusual crystal structures showing that threonyl-tRNA synthetase (ThrRS) is covalently inhibited by a natural product, obafluorin (OB). The residue forming a covalent bond with OB is a tyrosine in ThrRS active center, which is not commonly modified by covalent inhibitors. The two hydroxyl groups on the o-diphenol moiety of OB form two coordination bonds with the conserved zinc ion in the active center of ThrRS. Therefore, the beta-lactone structure of OB can undergo ester exchange reaction with the phenolic group of the adjacent tyrosine to form a covalent bond between the compound and the enzyme, and allow its nitrobenzene structure to occupy the binding site of tRNA. In addition, when this tyrosine was replaced by a lysine or even a weakly nucleophilic arginine, similar bonds could also be formed. Our report of the mechanism of a class of AARS covalent inhibitor targeting multiple amino acid residues could facilitate approaches to drug discovery for cancer and infectious diseases. Tyrosine-targeted covalent inhibition of a tRNA synthetase aided by zinc ion.,Qiao H, Xia M, Cheng Y, Zhou J, Zheng L, Li W, Wang J, Fang P Commun Biol. 2023 Jan 27;6(1):107. doi: 10.1038/s42003-023-04517-7. PMID:36707692 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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