Filamentation and inhibition of prokaryotic CTP synthase with ligands
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View abstract on PubMed
Summary
This summary is machine-generated.Cytidine triphosphate synthase (CTPS) is crucial for DNA and RNA synthesis. This study reveals its unique structure and binding in E. coli, offering insights for developing novel antibacterial drugs.
Area Of Science
- Biochemistry and Structural Biology
- Molecular Microbiology
- Drug Discovery
Background
- Cytidine triphosphate synthase (CTPS) is essential for de novo synthesis of CTP, a vital nucleotide for RNA and DNA.
- CTPS exhibits complex regulation, including filament formation, and is a potential therapeutic target against pathogens.
- Understanding prokaryotic CTPS structure is key for developing targeted inhibitors.
Purpose Of The Study
- To determine the high-resolution structure of *Escherichia coli* CTPS (ecCTPS) filament.
- To investigate the binding interactions of ecCTPS with CTP, NADH, and the inhibitor DON.
- To explore the evolutionary basis of CTPS filament formation and identify potential drug targets.
Main Methods
- Cryo-electron microscopy (cryo-EM) was used to determine the 2.9 Å resolution structure of the ecCTPS filament.
- Phylogenetic analysis was performed on filament-forming interfaces.
- Computational analysis, biochemical assays, and comparative structural analysis were employed.
Main Results
- The structure of the ecCTPS filament in complex with CTP, NADH, and DON was elucidated.
- A distinct CTP binding mode in ecCTPS compared to eukaryotic homologs was identified.
- Synergistic inhibition of CTPS by CTP with NADH or adenine was confirmed.
- A solvent-accessible ammonia tunnel was revealed upon DON binding.
Conclusions
- The study provides a detailed structural understanding of *E. coli* CTPS filament formation and regulation.
- The findings reveal unique aspects of ecCTPS CTP binding and synergistic inhibition mechanisms.
- This research lays the groundwork for designing specific inhibitors targeting prokaryotic CTPS for therapeutic applications.
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