In this multi-disciplinary work employing single-molecule TIRF microscopy, chemical biology and structural biology, researchers unveiled the molecular dance of DnaA at the replication origin using cryo-electron microscopy, in detail to near atomic resolution. Their findings reveal a previously unknown dinucleotide binding pocket within the DnaA oligomer, where two bases of a repeating DnaA-trio sequence tightly bind, enabling the capture of a single DNA strand. This key single DNA strand capture is the critical step that allows DnaA to pry open the DNA duplex, paving the way for the initiation of DNA replication. And the researchers’ work provides a molecular blueprint for how DnaA orchestrates this crucial step in bacterial replication, a fundamental process that underpins life itself.

 

This groundbreaking discovery significantly advances our understanding of bacterial replication, a fundamental process crucial for life. The unique mechanism we have unraveled presents a compelling target for developing new antibiotics, potentially leading to novel treatments for multi-antibiotic resistant bacterial infections. We continue to delve deeper into the intricate dance of DNA replication, paving the way for further breakthroughs in understanding bacterial cell biology and combating antibiotic resistance.