'Gel-to-Grid' cryoEM of membrane proteins using SMALP technology

自世纪中期显微镜问世以来，生物学家们一直在探讨那些往往比人类头发丝还要小许多倍的结构是如何支撑生命奇迹的。了解这些微小而精致的粒子的结构使我们能够解开自然的秘密。反过来，这些见解使我们能够在了解人类和动物疾病方面取得一些最重要的进展。例如，我们对病毒结构的了解使我们能够开发出更有效的疫苗，而蛋白质的结构则彻底改变了我们开发药物的速度。了解这些纳米尺度的结构也使我们能够回答一些最重要的科学问题，从遗传物质如何复制到肌肉如何工作。这些见解是通过在用于可视化这些小颗粒的方法上的定期突破而实现的。每一次突破都能让更多的细节更快地被看到，因为越来越多的样品越来越具有挑战性。想想看，在300年的时间里，我们已经能够从可视化细胞发展到科学家可以定期看到组成细胞的单个原子的排列。在伯明翰和沃里克的实验室里，我们一直在研究一种方法，这种方法将使我们能够可视化生物学中一些最重要的蛋白质的原子排列。这些蛋白质生活在细胞周围的膜中，并执行一些使细胞存活的重要工作。它们允许营养物质进入细胞并允许废物离开，它们还介导信号进出细胞的运动。这些功能使它们对研究人员非常感兴趣，但也许更重要的是，它们也是开发动物和人类健康新疗法的最重要目标。不幸的是，这些蛋白质已经被证明是非常难以研究的，并且在过去的50年里混淆了大量的科学家。2009年，我们发现了一种全新的方法来制造这些蛋白质，方法是使用一种简单的聚合物，这种聚合物更常见于汽车仪表板和油漆中。这种方法将蛋白质“包裹”在一个聚合物“带”中，使其保持稳定，使我们能够研究它。在这个项目中，我们将开发一种新的方法，使其更容易将这些聚合物带蛋白质转移到显微镜中，使它们能够成像。我们希望该方法将使这一过程比目前的方法容易得多，并将允许拍摄更多重要膜蛋白的图像。这将使我们能够对生物世界做出更完整的“原子图”，极大地帮助开发新的治疗方法。

Since the development of the microscope in the middle of the 17th century biologists have marvelled at how structures that are often many times smaller than the width of a human hair underpin the marvel of life. Understanding the structures of these tiny yet exquisitely formed particles has allowed us to unlock the secrets of nature. In turn these insights have allowed us to make some of the most important advances in our understanding of disease in humans and animals. For example, our understanding of the structure of viruses has allowed us to develop more effective vaccines while structures of proteins have revolutionised the speed with which we develop drugs. Understanding these nano-scale structures also allows us to answer some of the most important questions in science from how genetic material replicated to how muscles work. These insights have been enabled by regular breakthroughs in the methods used to visualise these small particles. Each breakthrough allows more detail to be seen more rapidly for more and more challenging samples. Just consider, in 300 years we have been able to move from visualising cells to a position where scientists can routinely see the arrangement of individual atoms that make up the cells. In our laboratories in Birmingham and Warwick we have been working on a method that will allow us to visualise the atomic arrangement of some of the most important proteins in biology. These proteins live in the membrane that surrounds cells and carry out some many essential jobs that allow cells to survive. They allow nutrients into the cell and allow waste products to leave, they also mediate the movement of signals into and out of the cell. These functions make them exceptionally interesting to researchers, but perhaps more importantly they are also the most important targets for developing new therapeutics for animal and human health. Unfortunately these proteins have proved to be exceptionally difficult to study and have confounded a large number of scientists over the past 50 years. In 2009 we found an entirely new way of making these proteins by using a simple polymer more commonly found in car dashboards and paint. This method "wraps" the protein in a polymer "belt" that keeps it stable allowing us to study it. In this project we am to develop a new method that will make it easier to transfer these polymer belted proteins into microscopes to allow them to be imaged. We hope that the method will make this process much easier than current methods and will allow more images to be taken of important membrane proteins. This should allow us the make a more complete "atomic picture" of the biological world greatly aiding the development of new therapeutics.