Fig. 6: Graphic models of E5-mediated initiation of viral genome replication.

a,b Model of the formation of the double hexameric E5 on the dsDNA. The red question marks indicate that the mechanism by which the two copies of E5 are loaded onto the dsDNA ends in the correct orientation and translocated along the dsDNA until they meet and initiate DNA melting is still unknown. c The inherent flexibility of the double hexameric conformation of E5, which may provide the internal triggers for the initiation of E5-mediated DNA melting. d ATP serves as an external trigger, inducing reorientation of the primase domain, triggering disruption of the E5 double hexamer and eventually leading to dissociation of E5 from dsDNA, although the mechanism underlying single-strand ejection requires further investigation. ATP binding in the primase and helicase domains is depicted as a red oval and two encircled blue S respectively. e The nucleotide cycling triggered non-classical escort translocation model of E5. The top view of the helicase domain of structures 1-5 was displayed with the spatial orientation of primase domains aligned. f The proposed model of primer synthesis and unwinding by E5 during DNA replication, with the red arrows representing the direction of E5 translocation along the leading strand and the red question marks indicating primer synthesis on the lagging strands.