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. The interferon response is a key component of the first line the host cellular defense to viral infection. Interfon-inducible human double-stranded RNA- dependent protein kinase (PKR) is a kinase that specifically phosphorylates translation initiation factor eIF2a in response to the presence of double-stranded (ds) RNA. PKR has been shown to be critical in regulating cellular response to viral pathogens, has been implicated in apoptosis, and its activity is down regulated in many cancers. There are currently no structural understandings for the linkage of RNA binding and kinase activity. The overall goal of this project is to understand the structural origins of PKR recognition and activation by virally encoded 5? UTR transcripts in viral genomes such as HIV and HCV. Rapid access to BL4-2 Bio SAXS/D will help to provide an immediate structural context of how PKR?RNA recognition occurs. Previously solved structures of the individual PKR domains will be modeled into the data provided by SAXS/D for the full-length protein, aiding in the development of a new model of PKR recognition and activation by RNA.
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