Every cell in the human body is wrapped in an oily membrane, and the proteins embedded in that membrane act as gatekeepers—controlling what enters, what leaves, and how cells communicate. These membrane proteins must switch between open and closed states, like a tap, but standard imaging techniques only capture a single frozen snapshot of the protein at a time. This project aims to develop a new method to watch those proteins move in real time, revealing exactly how they transition between states. The researchers will focus on two systems: human pain receptors and bacterial proteins that help microbes survive osmotic stress. If successful, this work could directly inform the design of better painkillers and new antibiotics that target these specific protein motions. The research is fundamental science—it seeks a deeper understanding of how membrane proteins work at the atomic level. Past breakthroughs in protein crystallography have already led to many drugs; this project extends that approach by adding the dimension of movement, which could unlock treatments for diseases where membrane proteins malfunction.
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Although life requires water, life must be able to control the flow of water. As an example, if a person (70% water) jumps into a swimming pool they do not dissolve like a sugar cube. This is because we have a barrier between the swimming pool water and the water inside our cells. This barrier is the membrane or lipid bilayer, it is made of oily compounds. The bilayer is essential it keeps important things in and poisonous things out. All organisms have these bilayers. On their own bilayers would simply block all transport, thus we could not take up nutrients nor could we get rid of waste. Proteins embedded in this membrane are thus needed to act as gate keepers to control movements of ions, nutrients, waste and proteins across the lipid bilayer. These proteins are also the telephone connections between one cell and another. The nerve impulse in humans transmits trigger release of a transmitter (small chemical) from the neuron. The transmitter interacts with another cell by promoting some change in the cell, each cell uses membrane proteins as part of this process. Membrane proteins that control ions movement across the bilayer are called ion channels. They must, like a tap, be able to fully closed to stop leaks but they must also open when required. Many diseases are caused by membrane proteins not working properly. If we are to treat these diseases we need to understand how membrane proteins work. Protein crystallography has transformed our understanding of proteins. It allows us to see every atom in the structure and understand a great deal about the function of the protein. This scientific approach has led to the development of many new drugs. However, this technique can only see one state of the protein at a time. We propose to develop a new approach that will allow us to see in detail exactly how membrane proteins move between the open and closed states. We have chosen to study the pain receptors in humans and the osmotic stress survival proteins in bacteria. These are important systems with obvious medical benefits, treatment of pain and design of new antibiotics.
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