Abstract:
Grb2 is an important regulator of normal vs. oncogenic cell signaling transduction. It plays a pivotal role on kinase-mediated signaling transduction by linking Receptor Tyrosine kinases to Ras/MAPK pathway which is known to bring oncogenic outcome. Coumarins are phenolic molecules found in several plants and seeds widely studied because of the antibiotic, anti-inflammatory, anticoagulant, vasodilator, and anti-tumor properties. Despite several studies about the anti-tumor properties of Coumarin in vivo and the role of Grb2 in signaling pathways related to cell proliferation, a molecular level investigation of the interaction between Grb2 and Coumarin is still missing. In this study, we performed a combined set of biophysical approaches to get insights on the interaction between Grb2 in a dimer state and Coumarin. Our results showed that Coumarin interacts with Grb2 dimer through its SH2 domain. The interaction is entropically driven, 1:1 molecular ratio and presents equilibrium constant of 105 M-1. In fact, SH2 is a well-known domain and a versatile signaling module for drug targeting which has been reported to bind compounds that block Ras activation in vivo. Despite we don\'t know the biological role coming from interaction between Grb2-SH2 domain and Coumarin, it is clear that this molecule could work in the same way as a SH2 domain inhibitor in order to block the link of Receptor Tyrosine kinases to Ras/MAPK pathway.
摘要:
Grb2是正常与正常的重要调节器致癌细胞信号传导。它通过将受体酪氨酸激酶与Ras/MAPK途径连接而在激酶介导的信号转导中起关键作用,该途径已知会带来致癌结果。香豆素是在几种植物和种子中发现的酚类分子,由于抗生素而被广泛研究,抗炎,抗凝剂,血管扩张剂,和抗肿瘤特性。尽管有一些关于香豆素在体内的抗肿瘤特性以及Grb2在与细胞增殖相关的信号通路中的作用的研究,关于Grb2和香豆素之间相互作用的分子水平研究仍然缺失。在这项研究中,我们进行了一组组合的生物物理方法,以深入了解二聚体状态的Grb2与香豆素之间的相互作用。我们的结果表明,香豆素通过其SH2结构域与Grb2二聚体相互作用。相互作用是熵驱动的,1:1的分子比,并且呈现105M-1的平衡常数。事实上,SH2是众所周知的结构域和用于药物靶向的通用信号传导模块,已报道其结合体内阻断Ras激活的化合物。尽管我们不知道Grb2-SH2结构域和香豆素之间相互作用的生物学作用,很明显,该分子可以以与SH2结构域抑制剂相同的方式起作用,以阻断受体酪氨酸激酶与Ras/MAPK途径的连接。