Dissecting the dsDNA viral packaging machinery: structural evolution and potential for therapeutics

Some double-stranded DNA viruses, such as herpesviruses and bacteriophages, utilize a powerful molecular motor to package DNA into their capsids to liquid-crystalline density. The motor is composed of large and small terminase subunits that bind to a portal complex located at a unique vertex on the icosahedral capsid. The small terminase is critical for recognition of the viral genomic DNA. The enzymatic component of the motor is the large terminase that has two functional domains necessary for ATP hydrolysis and DNA cleavage. Bacteriophage large terminase amino acid sequences are highly divergent, but their overall structural architecture and function are conserved across both tailed bacteriophages and herpesviruses. There are limited antiviral drugs for herpesvirus infections. Therefore, the viral DNA packaging motor is being investigated as an alternative drug target. In this review, we discuss the past and recent genetic, biochemical, and structural research on viral terminase motors that has illuminated their role in DNA packaging and potential as candidates for antiviral drug targeting.