8zx0 | pdb_00008zx0
Crystal Structure of CntL in complex with a dual-site inhibitor
Structural highlights
FunctionNASLD_STAAM Catalyzes the nucleophilic attack of one alpha-aminobutanoate moiety from SAM onto D-histidine to produce the intermediate (2S)-2-amino-4-{[(1R)-1-carboxy-2-(1H-imidazol-4-yl)ethyl]amino}butanoate. Functions in the biosynthesis of the metallophore staphylopine, which is involved in the acquisition of nickel, cobalt, zinc, copper, and iron, and thus enables bacterial growth inside the host, where metal access is limited. Therefore, this enzyme probably contributes to staphylococcal virulence (PubMed:27230378, PubMed:29091735). Appears to be specific for D-histidine as substrate (PubMed:29091735).[1] [2] Publication Abstract from PubMedTo survive in the metal-scarce environment within the host, pathogens synthesize various small molecular metallophores to facilitate the acquisition of transition metals. The cobalt and nickel transporter (Cnt) system synthesizes and transports staphylopine, a nicotianamine-like metallophore, and serves as a primary transition metal uptake system in Gram-positive bacteria including the human pathogen Staphylococcus aureus. In this study, we report the design of the first inhibitor of the Cnt system by targeting the key aminobutanoyltransferase CntL which is involved in the biosynthesis of staphylopine. Through structure-guided fragment linking and optimization, a class of acceptor-adenosine dual-site inhibitors against S. aureus CntL (SaCntL) were designed and synthesized. The most potent inhibitor, compound 9, demonstrated a DeltaT(m) value of 9.4 degrees C, a K(d) value of 0.021 +/- 0.004 muM, and an IC(50) value of 0.06 muM against SaCntL. The detailed mechanism by which compound 9 inhibits SaCntL has been elucidated through a high-resolution co-crystal structure. Treatment with compound 9 resulted in a moderate downregulation of intracellular concentrations of iron, nickel, and cobalt ions in the S. aureus cells cultured in the metal-scarce medium, providing the first chemical validation of the important role of Cnt system in bacterial metal acquisition. Our findings pave the way for the development of CntL-based antibacterial agents in future. Structure-guided inhibitor design targeting CntL provides the first chemical validation of the staphylopine metallophore system in bacterial metal acquisition.,Luo Z, Su J, Luo S, Ju Y, Chen B, Gu Q, Zhou H Eur J Med Chem. 2024 Oct 22;280:116991. doi: 10.1016/j.ejmech.2024.116991. PMID:39442338[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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