NMR/MD Studies of Human MDM2 Interaction with P53

描述(由申请人提供)：癌蛋白MDM2作为潜在的治疗靶点特别令人感兴趣，因为它在调节P53活性方面起着关键作用。已经鉴定了几种能够破坏p53-MDM2相互作用的小分子配体，但目前对它们对MDM2结构和动力学的影响以及这可能对其治疗效果的影响的了解很少。MDM2的动态结构以及P53肽或小分子配体结合如何影响MDM2的动态结构将通过核磁共振松弛和分子动力学模拟研究来表征。剩余偶极耦合测量将揭示配体结合对MDM2平均溶液结构的影响。通过对分子动力学轨迹的分析和与核磁共振动力学测量的比较，可以预测相关主链和/或侧链动力学的远程网络。这项研究将为配体结合如何改变MDM2结构及其生物活性提供有用的线索。在更广泛的背景下，从这项研究中获得的知识将对试图为其他蛋白质设计紧密结合化合物的研究人员具有普遍意义。

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.