Structural Studies of the pRB Tumor Suppressor Complexed with Human Papillomavirus E7 Proteins.
Abstract
Since viral oncoproteins are expected to compete with and imitate interactions that pRB has with cyclin DI, understanding high affinity pRB-viral oncoprotein complexes will provide tremendous insight into the specific interactions required for the development of small compounds that can destabilize pRB-cyclin DI complexes in cyclin DI-mediated breast cancer. Therefore, the primary goal of this project is to determine the three dimensional structure of pRB bound HPV E7 and Adenovirus 5 ElA. Additionally, since p53 functions as a tumor suppressor that is often inactivated in breast cancer, a secondary goal of this project is to determine the structure of the PCAF acetyltransferase domain with coenzyme A and a p53-derived peptide in order to gain insight into PCAF-mediated p53 activation This study demonstrates that bacterially coexpressed pRB(376-792) and viral oncoproteins form complexes These purified complexes probably have resisted crystallization because pRB(376-792) includes a flexible linker region between two structured domains of pRB. Therefore, a new "linkerless" pRB construct has been generated for future pRB/viral oncoprotein crystallization trials. Additionally, crystallography of HPVla E7 and NMR studies of Adenovirus S ElA have had preliminary success. The crystal structure of PCAF bound to coenzyme A has been solved and provides insight into PCAF-mediated p53 acetylation and activation.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 1999
- Accession Number
- ADA374151
Entities
People
- Adrienne M. Cements
Organizations
- Wistar Institute