NMR/MD Studies of Human MDM2 Interaction with P53

描述（由申请人提供）：由于其在调节p53活性中的关键作用，癌蛋白MDM 2作为潜在的治疗靶点具有特殊意义。 已经表征了能够破坏p53 -MDM 2相互作用的几种小分子配体，但是目前对它们对MDM 2的结构和动力学的影响的理解，以及这可能对它们的治疗效果的影响是最小的。 MDM 2的动态结构以及它如何受到p53肽或小分子配体结合的影响将通过结合NMR弛豫和分子动力学模拟研究来表征。 残余偶极耦合测量将揭示配体结合对MDM 2的平均溶液结构的影响。 相关的主链和/或侧链动力学的长程网络将预测从分子动力学轨迹分析和NMR动力学测量的比较。 这项研究将为配体结合如何改变MDM 2的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通用性。

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.