: The long-term goal of this research program is to understand the structures and energetics of the macromolecular interactions that control critical steps in the life cycle of papillomaviruses associated with human carcinomas. We have determined the three-dimensional structures of the DNA-binding domain of the transcriptional regulatory E2-proteins from viral strains HPV-16, HPV-18 and BPV-1, free and complexed to DNA. In parallel functional studies, we have defined the relationship between DNA conformational properties and the ability of the E2 proteins to recognize and bind to specific sites on the papillomavirus genomes. These studies provide a chemical perspective on fundamental biological processes of an important human pathogen and a foundation for the design of therapeutic strategies. This renewal application continues and extends our structural and functional analyses of the protein-DNA complexes and the multi-protein-DNA complexes that regulate viral transcription and replication.