HIGH RESOLUTION STRUCTURE OF HERPESVIRUS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Herpesvirus is one of the largest families of human and animal viruses. Infection by these viruses can cause a variety of diseases including disseminated disease in the newborn, cold sores, cutaneous lesions, mononucleosis, non-epidemic encephalitis in adults, retinitis, and cancer. DNA packaging is a key step during the replication of herpesvirus and many double-stranded DNA (dsDNA) bacteriophages. The DNA packaging machinery consists of two basic components: a terminase and a portal protein. The terminase catalyzes the DNA packaging by cleaving genome-length DNA from concatemers and providing the energy for the packaging reaction. The terminase contains two subunits: a DNA-recognition subunit that specifically binds to the viral concatemeric DNA, and a catalytic subunit that cleaves the genome-length DNA from the concatemer. The DNA is then injected into a pre-formed capsid through a conduit formed by the ring-like portal protein complex, powered by the catalytic subunit of the terminase. The proposed research is aimed at high resolution structural studies on the terminase of HSV-1 by X-ray crystallography and cryoEM. The interactions between the terminase/portal and the capsid will be explored. The structures will open avenues to novel measures to control and prevent infection and diseases caused by herpesvirus. The proposed research will determine the X-ray structure of pUL15 of the HSV-1 terminase, perform the cryoEM image reconstruction of the HSV-1 capsids, investigate the assembly of the terminase, portal complex, and the capsid, and propose a detailed model for the DNA packaging mechanism in HSV-1.