Research Fellows Directory
Dr Richard Bayliss
University of Leicester
A human cell undergoes a spectacular transformation as it enters mitosis, the phase of its existence just before it divides into two daughter cells. The membrane that surrounds its nucleus dissolves, its DNA condenses to form ‘X’ shapes, and the mitotic spindle is formed. The spindle is a molecular machine that ensures that each daughter cell receives the correct amount of DNA and is made up of hundreds of proteins, some of which form long fibres. Errors in the spindle’s workings are associated with cancer. The aim of my research is to find out how the mitotic spindle works and to develop novel cancer drugs based on this knowledge.
My team uses X-ray crystallography to reveal the workings of the mitotic spindle at the level of the individual atoms within its constituent proteins. Accurate mitotic spindle assembly requires the regulated activity of a class of proteins called kinases, which modify other proteins such as those responsible for building the spindle. This changes the properties of the modified protein, such as its location within the cell. We recently discovered that one of these kinases, called Nek7, has a switch that keeps the protein inactive until the cell is ready to divide. The structure of Nek7 revealed precisely which atoms form the switch, and we were able to produce a version of Nek7 that lacked the switch. This version of Nek7 is always active, causing cells to die more frequently, showing that the activity of Nek7 must be strictly controlled to keep cells healthy. We discovered the identity of another protein that is needed to switch Nek7 ‘on’, and we are in the process of working out the details of the mechanism. Some related proteins, such as Nek2, have the same set of atoms that form the switch in Nek7, but these have only ever been seen in the ‘on’ position. Intriguingly, we synthesized a drug-like molecule that brings the Nek2 switch into the ‘off’ position, and we believe that these could form the basis for future cancer drugs.
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