NMR/MD Studies of Human MDM2 Interaction with P53

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): The oncoprotein MDM2 is of special interest as a potential therapeutic target due to its critical role in regulating p53 activity. Several small molecule ligands capable of disrupting the p53 - MDM2 interaction have been characterized, but the current understanding of their influence on the structure and dynamics of MDM2, and what implications this may have for their therapeutic effectiveness, is minimal. The dynamic structure of MDM2 and how it is influenced by p53 peptide or small molecule ligand binding will be characterized through combined NMR relaxation and Molecular Dynamics simulation studies. Residual Dipolar Coupling measurements will reveal the effect ligand binding has on the average solution structure of MDM2. Long range networks of correlated backbone and/or side chain dynamics will be predicted from analysis of Molecular Dynamics trajectories and comparison with NMR dynamics measurements. This research will provide useful clues as to how ligand binding will change the MDM2 structure and its biological activities. In a broader context, the knowledge gained from this research will be of general utility for researchers attempting to design tight binding compounds for other proteins as well.