8ZX0
Crystal Structure of CntL in complex with a dual-site inhibitor
This is a non-PDB format compatible entry.
Summary for 8ZX0
| Entry DOI | 10.2210/pdb8zx0/pdb |
| Descriptor | D-histidine 2-aminobutanoyltransferase, (2S)-2-[2-[[(2S,3S,4R,5R)-5-(6-azanyl-2-chloranyl-purin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methylsulfanyl]ethylamino]-3-(1H-imidazol-4-yl)propanoic acid, 1,2-ETHANEDIOL, ... (6 entities in total) |
| Functional Keywords | transferase, inhibitor |
| Biological source | Staphylococcus aureus subsp. aureus Mu50 |
| Total number of polymer chains | 2 |
| Total formula weight | 65444.81 |
| Authors | |
| Primary citation | Luo, Z.,Su, J.,Luo, S.,Ju, Y.,Chen, B.,Gu, Q.,Zhou, H. Structure-guided inhibitor design targeting CntL provides the first chemical validation of the staphylopine metallophore system in bacterial metal acquisition. Eur.J.Med.Chem., 280:116991-116991, 2024 Cited by PubMed Abstract: To 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 ΔT value of 9.4 °C, a K value of 0.021 ± 0.004 μM, and an IC value of 0.06 μM 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. PubMed: 39442338DOI: 10.1016/j.ejmech.2024.116991 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.091 Å) |
Structure validation
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