A great deal is known about the E. coli initiator protein, DnaA, even though its high resolution structure has not yet been determined. Considerable structure-function information has been obtained from biochemical studies and sequence comparisons with other proteins. Based on this information, the DnaA protein can be divided into four functional domains, which are numbered I to IV starting at the amino terminus.

    Each domain plays a critical role in the initiation of DNA synthesis. Domain I participates in DnaA oligomerization and also helps to recruit the DnaB protein, a helicase containing six identical subunits that is required to unwind the double helix so that DNA synthesis can be initiated. Domain ∏binds the Dna8 helicase transiently. Domain Ⅲ binds ATP or ADP and has an ATPase activity. The DnaA · ATP complex is essential for replication initiation. Domain IV binds to the replicator and helps to unwind the double helix so that the DnaB can be loaded onto the single strands that are generated. It also contains a membrane binding site that interacts with anionic glycerophospholipids in the cell membrane. This interaction facilitates the conversion of the DnaA · ADP complex to the DnaA · ATP complex, an essential step that must take place before a new round of replication can begin.