A Double Dose - Steroid Dimers for Synthetic Signal Transduction

该项目旨在开发一种替代形式的跨膜信号转导，利用一种新的分子工具：刚性杆分子转子。我们将创建一个具有限制移动的移动类型系统。该项目将利用PI团队最近的工作，该团队利用构象变化开辟了一条通往人工信号转导的道路，提供了视紫红质和其他G蛋白偶联受体的光开关模拟物。我们熟悉宏观世界中我们周围的工具，从复杂的机器（例如计算机）到简单的组件（例如转子）。还有一个生物分子机器（通常是蛋白质）的世界，它们在细胞中运作，并介导许多生命的基本过程。其中一个过程是信息和分子穿过细胞膜的传输，细胞膜是一个几纳米厚的保护屏障。专门的跨膜蛋白，如G蛋白偶联受体，识别外部化学信使（“信号”），并将其转化为细胞内的化学信息（“报告”），这一过程通常涉及蛋白质形状（构象）的变化。该项目旨在使用多纳米长的刚性杆分子转子开发一种跨膜传输信息的新方法。这些完全人造的分子转子将被设计成在与外部化学“信号”结合后改变形状。这种形状变化将通过合成和天然膜传递信号中的信息。该项目将使用合成超分子化学来打开通往人工信号转导的途径。该项目将使用合成有机化学来创建一个二聚体家族，每个二聚体将带有不同的“报告”基团，例如荧光染料，催化剂和蛋白质/酶抑制剂。在首先表征这些化合物在有机溶剂中的行为之后，然后将在简单的细胞模拟物（磷脂囊泡）的膜中研究它们。除了培养合成和超分子化学方面的技能外，该项目还提供了在化学生物学和生物化学方面工作的机会。学生将学习细胞培养技术，因为最后一个阶段涉及研究哺乳动物细胞膜中这些分子转子的行为。如果成功，该系统将成为一个真正的合成生物学平台，将带来许多令人兴奋的机会，例如提供人工信号网络，重新编程细胞并产生基础科学见解。

This project aims to develop an alternative form of transmembrane signalling that utilises a new molecular tool: rigid-rod molecular rotors. We will create a lever-type system with restricted movement. This project will capitalise on recent work from the PI's group that has used conformational change to open a path towards artificial signal transduction, providing light-switchable mimics of rhodopsin and other G-protein coupled receptors.We are familiar with the tools around us in the macroscopic world, from complex machines (e.g. computers) to simple components (e.g. rotors). There also exists a world of biological molecular machines (typically proteins) that operate in cells and mediate many of life's fundamental processes. One of these processes is the transmission of information and molecules across the cell membrane, a protective barrier that is several nanometres thick. Specialised transmembrane proteins, such as G-protein coupled receptors, recognise external chemical messengers ('signals') and turn these into chemical information ('reports') inside the cell, in a process that usually involve a change in protein shape (conformation). This project aims to use multi-nanometre long rigid-rod molecular rotors to develop a new way of transmitting information across membranes. These entirely artificial molecular rotors will be designed to change shape after binding to an external chemical 'signal'. This shape change will transmit the information in the signal across both synthetic and natural membranes. This project will use synthetic supramolecular chemistry to open a pathway towards artificial signal transduction.The project will employ synthetic organic chemistry to create a family of dimers, each of which will bear a different 'reporting' group, such as a fluorescent dye, catalyst, and protein/enzyme inhibitor. After first characterising the behaviour of these compounds in organic solvents, they will then be studied in the membranes of simple cell mimics (phospholipid vesicles). As well as developing skills in synthetic and supramolecular chemistry, the project provides the opportunity to work in chemical biology and biological chemistry. The student will learn cell culture techniques, as the last stage involves studying the behaviour of these molecular rotors in mammalian cell membranes. If successful, this system would be a truly synthetic biology platform that will lead to many exciting opportunities, for example providing artificial signalling networks that reprogram cells and produce fundamental scientific insights.