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

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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.