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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA066964-08
Application #
6633135
Study Section
Virology Study Section (VR)
Program Officer
Wong, May
Project Start
1996-02-21
Project End
2006-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
8
Fiscal Year
2003
Total Cost
$245,680
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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Kim, Seung-Sup; Zhang, Rong-guang; Braunstein, Steve E et al. (2002) Structure of the retinal determination protein Dachshund reveals a DNA binding motif. Structure 10:787-95
Kim, S S; Tam, J K; Wang, A F et al. (2000) The structural basis of DNA target discrimination by papillomavirus E2 proteins. J Biol Chem 275:31245-54
Hegde, R S; Androphy, E J (1998) Crystal structure of the E2 DNA-binding domain from human papillomavirus type 16: implications for its DNA binding-site selection mechanism. J Mol Biol 284:1479-89
Hines, C S; Meghoo, C; Shetty, S et al. (1998) DNA structure and flexibility in the sequence-specific binding of papillomavirus E2 proteins. J Mol Biol 276:809-18
Rozenberg, H; Rabinovich, D; Frolow, F et al. (1998) Structural code for DNA recognition revealed in crystal structures of papillomavirus E2-DNA targets. Proc Natl Acad Sci U S A 95:15194-9
Hegde, R S; Wang, A F; Kim, S S et al. (1998) Subunit rearrangement accompanies sequence-specific DNA binding by the bovine papillomavirus-1 E2 protein. J Mol Biol 276:797-808