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 Dl, 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 Dl complexes in cyclin Dl -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 El A. 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. To date, these purified complexes have resisted crystallization. However, crystallography of HPV 1 a E7 and NMR studies of Adenovirus 5 El A have had preliminary success. Sedimentation equilibrium experiments of the pRB/viral oncoprotein complexes and their individual components have been utilized to characterize protein oligomerization states. Additionally, 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
- Jul 01, 2000
- Accession Number
- ADA387831
Entities
People
- Adrienne Clements
Organizations
- University of Pennsylvania