Molecular mechanism of genome packaging by dsDNA viruses

Every virus in the dsDNA family—from the gut-infecting crAssphage to the poxvirus that causes smallpox—must pack its genetic material into a protein shell with the precision of a mechanical press, and this project will use cryo-electron microscopy to watch exactly how the molecular motor that does the packing works. The problem is that while we know these viruses use a protein called terminase to force DNA into their capsids, the structural details of how the motor grips, ratchets, and pushes the DNA are unknown. Without that atomic-level picture, we cannot design drugs that jam the motor. The work will also tackle a second, unrelated class of DNA-packing motors found in viruses like the poxvirus family, which use a different protein (FtsK-like) to achieve the same result. This is fundamental science. If it succeeds, it will reveal the precise mechanics of a process essential to thousands of virus species. That structural knowledge could eventually inform the design of broad-spectrum antiviral compounds that block DNA packaging—a step that would affect how we treat infections ranging from gut viruses to poxviruses. But the immediate payoff is a deeper understanding of how molecular machines convert chemical energy into mechanical work.