Probing transcriptional activation at the molecular level

项目摘要 转录机器的大部分组装过程由瞬时和动态蛋白质控制， 蛋白质相互作用（PPI），无视标准的表征策略。转录辅激活因子是 这一过程的枢纽，与转录激活因子，表观遗传调节因子，聚合酶和其他 辅激活子来组装转录机器。辅活化剂也代表了一个中心的分子识别 这是一个难题，因为它们与具有结合伴侣的如此多样化的阵列相互作用的机制， 局部结合相互作用对长程结构和功能轨迹的影响。上一 在资助期间，我们开发了一个分子识别模型，解决了难题的第一部分。这里 将建立在这个模型上，以发现以前标记为不可药用的辅激活剂的变构调节剂， 他们的核心职能。此外，我们将回答这个难题的后半部分， 转录辅激活因子功能中分子识别的综合模型。

Project Summary Much of the assembly process of the transcription machinery is governed by transient and dynamic protein- protein interactions (PPIs) that defy standard characterization strategies. Transcriptional coactivators are the hubs of this process, interacting with transcriptional activators, epigenetic modulators, the polymerase, and other coactivators to assemble the transcriptional machine. Coactivators also represent a central molecular recognition conundrum, as the mechanisms by which they interact with such a diverse array with binding partners and the influence of local binding interactions on longer-range structural and functional trajectories. In the previous funding period, we developed a molecular recognition model that addresses the first part of the conundrum. Here will build on this model to discover allosteric modulators of coactivators previously labelled undruggable despite their central functional roles. Additionally, we will answer the latter half of the conundrum to develop a comprehensive model of molecular recognition in transcriptional coactivator function.