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 β-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.
Understanding soil microbial element limitation and its relation with the microbial community can help in elucidating the soil fertility status and improving nutrient management of planted forest ecosystems. The stand age of a planted forest determines the aboveground forest biomass and structure and underground microbial function and diversity. In this study, we investigated 30 plantations of Camellia oleifera distributed across the subtropical region of China that we classified into four stand ages (planted <9 years, 9–20 years, 21–60 years, and >60 years age). Enzymatic stoichiometry analysis showed that microbial metabolism in the forests was mainly limited by C and P. P limitation significantly decreased and C limitation slightly increased along the stand age gradient. The alpha diversity of the soil microbiota remained steady along stand age, while microbial communities gradually converged from scattered to clustered, which was accompanied by a decrease in network complexity. The soil bacterial community assembly shifted from stochastic to deterministic processes, which probably contributed to a decrease in soil pH along stand age. Our findings emphasize that the stand age regulated the soil microbial metabolism limitation and community assembly, which provides new insight into the improvement of C and P management in subtropical planted forest.
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