Dissecting the Viral Large Terminase: Structural Evolution and Prospects for

Some double-stranded DNA viruses utilize a powerful molecular motor to package DNA 13 into their capsids to liquid-crystalline density. The motor is composed of a portal complex and 14 large and small terminase subunits. The enzymatic component of the motor is the large terminase 15 that has two functional domains necessary for ATP hydrolysis and DNA cleavage. Large terminase 16 amino acid sequences are highly divergent, but their overall structural architecture and function 17 are conserved across tailed bacteriophages and herpesviruses. Because there are limited antiviral 18 drugs for herpesvirus infections, and these exclusively target the viral DNA polymerase, cross-19 resistance is of high concern. Therefore, the DNA packaging motor is being investigated as an 20 alternative drug target. In this review, we discuss the past and recent genetic, biochemical, and 21 structural research on large terminases that has illuminated their role in DNA packaging and 22 potential as a candidate for antiviral drug targeting. 23