Structure/function analysis of the Ral/RLIP signalling pathway as a therapeutic target

我们的工作解决了细胞内参与信号传导的蛋白质结构和功能之间的关系。这些蛋白质控制着许多在癌症和其他疾病中失控的信号传递途径。我们研究的蛋白质在细胞从正常到癌变的过程中很重要，这个过程需要增加生长和抵抗正常细胞死亡的结合。我们在这里集中讨论的蛋白质RLIP-76参与了许多过程。它对应激反应很重要，对将分子带入细胞也很重要，这是一个严格控制的过程。这两种途径在癌症进展中都很重要。RLIP-76还可以作为一个泵，将化疗药物从细胞中移除，使其效果降低。如果我们能够更多地了解RLIP-76如何在所有这些不同的过程中被激活，我们可能能够找到抑制它的方法；所以我们要研究的一件事是RLIP-76的激活机制。蛋白质在细胞中做的最重要的事情之一就是与其他蛋白质结合。虽然我们知道RLIP-76与哪些蛋白质结合，但我们不知道它是如何与它们结合的。因此，我们研究的另一个主要目标是了解RLIP-76如何与这些其他蛋白质结合。我们通过计算RLIP-76及其伙伴的复合体在三维空间中的样子来做到这一点。这是至关重要的，因为如果我们知道蛋白质是如何相互结合的，以及蛋白质的哪些特定区域对相互作用很重要，就有可能设计出防止或增强这种结合的药物，

Our work addresses the relationship between structure and function in proteins involved in signalling within the cell. These proteins control many signal transmission pathways that become deregulated in cancer and other diseases. The proteins that we study are important in the progression of a cell from being normal to being cancerous, a process that requires a combination of increased growth and resistance to normal cell death. The protein that we are proposing to concentrate on here, RLIP-76, is involved in many processes. It is important for stress responses and also for bringing molecules into the cell, a process that is strictly controlled. Both of these pathways are important in cancer progression. RLIP-76 can also act as a pump that removes chemotherapy drugs from cells, making them less effective. If we can understand more about how RLIP-76 is activated in all of these different processes, we might be able to find ways to inhibit it; so one of the things we will look at is the mechanism of RLIP-76 activation. One of the most important things that proteins do in cells is to bind to other proteins. Although we know which proteins RLIP-76 binds to, we do not know how it binds to them. So one of the other major aims of our research is to understand how RLIP-76 binds to these other proteins. We do this by working out what the complex of RLIP-76 and its partner looks like in three dimenensions. This is crucial, because if we know how proteins bind to each other and which particular regions of the proteins are important for the interaction, it will be possible to design drugs that either prevent or enhance this binding,