TARGETING HER-2 PROTEIN FOR BREAST CANCER USING COMPUTATIONAL APPROACH

这个子项目是利用资源的许多研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 为子项目列出的总成本可能 代表子项目使用的中心基础设施的估计数量， NCRR赠款不直接向子项目或子项目工作人员提供资金。 本研究项目的长期目标是了解蛋白质胞外结构域在蛋白质-蛋白质相互作用中的作用，以促进细胞信号传导。本项目的短期目标是了解HER 2胞外结构域的结构域-4在蛋白质-蛋白质相互作用（PPI）中与其他表皮生长因子受体在细胞生长信号传导中的作用。假设蛋白质-蛋白质相互作用表面具有本质上疏水的小核心区域，并且蛋白质-蛋白质相互作用可以通过与核心区域相互作用的小分子来调节，以调节细胞生长的信号传导。作为一个模型系统，我们研究了人表皮生长因子受体胞外结构域的蛋白质-蛋白质相互作用。EGFR的胞外结构域由四个结构域组成，其中结构域-2和结构域-4已知参与二聚化过程。结构域-4在二聚化中的重要性尚不清楚。因此，这些蛋白质将作为理解细胞信号传导的蛋白质-蛋白质相互作用的良好模型。阻断HER 2蛋白的结构域-4具有临床意义，因此，拟议研究的结果可作为“转化研究”。“使用计算对接方法，提出了HER 2-EGFR异源二聚体的模型。通过表面等离子体共振研究EGFR-HER 2、HER 2-HER 3之间蛋白质-蛋白质相互作用的破坏。利用光谱和荧光分析研究了一种靶向PPI疏水核心区的疏水小分子。结果表明，靶向HER 2蛋白结构域-4的疏水部分的小分子破坏EGFR-HER 2和HER 2-HER 3之间的PPI。未来的研究将使用实验和计算方法来了解EGFR，HER 2和HER 3中PPI的疏水核心区域。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The long-term objective of this research project is to understand the role of extracellular domains of proteins in protein-protein interactions for cell signaling. The short-term objective of this project is to understand the role of domain-4 of HER2 extracellular domain in protein-protein interactions (PPI) with other epidermal growth factor receptors in signaling for cell growth. The hypothesis is that protein-protein interaction surfaces have small core regions that are hydrophobic in nature and protein-protein interactions can be modulated by small molecules that interact with core regions to modulate the signaling for cell growth. As a model system we investigate the protein-protein interaction of human epidermal growth factor receptor extracellular domains. The extracellular domain of EGFRs consists of four domains, of which domain-2 and domain-4 are known to be involved in dimerization process. The importance of domain-4 in dimerization is not understood. Hence, these proteins will serve as a good model for understanding protein-protein interactions for cell signaling. Blocking of domain-4 of HER2 protein has clinical significance and thus the results from the proposed research can be applicable as "translational research." Using computational docking methods, a model was proposed for HER2-EGFR heterodimer. The disruption of protein-protein interactions between EGFR-HER2, HER2-HER3 were investigated by surface plasmon resonance studies. A small hydrophobic molecule that was targeted towards the hydropbobic core region in PPI was also studied using spectroscopic and fluorescence assasys. Results suggested that a small molecule targeted to the hydrophobic part of domain-4 of HER2 protein disrupts the PPI between EGFR-HER2 and HER2-HER3. Future studies will be carried out to understand the hydrophobic core regions of the PPI in EGFR, HER2 and HER3 using experimental and computational methods.