Mitotic Regulation and Cancer Team
Team Leader: Dr Richard Bayliss
Location: Chester Beatty Laboratories, London
Section: Section of Structural Biology
Crystals of the protein kinase Aurora-A
A 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 chromosomes (DNA) condense to form ‘X’ shapes, and its microtubules, which form part of the cell’s internal transport network, re-organise to form the mitotic spindle. The spindle is a molecular machine that ensures that each daughter cell receives the correct amount of DNA. Errors in the spindle’s workings are associated with cancer because they can create large-scale re-arrangements of chromosomes. As well as microtubules, spindles are made up of hundreds of other proteins that work together to minimize errors. We do not understand the individual role of most of these proteins or how they work together to make a spindle. The aim of my research is to resolve the workings of the mitotic spindle at the molecular level, and to develop novel cancer drugs that target malfunctioning spindles.
X-ray crystal structure of the protein kinase Nek7 (orange ribbon) with adenosine diphosphate (pink spheres) bound to its active site
My team uses X-ray crystallography to resolve the position of every atom within the three-dimensional structures of proteins involved in spindle assembly. These structures reveal the workings of the mitotic spindle at the level of individual atoms, and form the basis for interpreting what happens in inaccurate spindle formation. Accurate mitotic spindle assembly requires the regulated activity of many proteins in the cell, in particular enzymes such as kinases. These enzymes are an important part of regulation in the cell because they modify other proteins such as those responsible for building the spindle. The modified proteins have changed properties. In normal cells, the activity of kinases such as Aurora-A and Nek7 that control mitotic spindle assembly is strictly regulated by many other proteins. In cancerous cells, however, the enzymes may be activated erroneously, allowing the cell to divide out of control.
Many of the enzymes involved in spindle assembly are potential drug targets, and my basic research informs the strategy by which they are targeted in the development of cancer drugs. Together with colleagues in different departments, my team helps produce compounds that target protein kinases. X-ray crystallography accelerates the design of better drugs because the drug-enzyme structure enables us to see what improvements need to be made.
More detailed information about the work of the team is available on their homepage.
The group receives funding from The Royal Society, Cancer Research UK, MRC, Breakthough Breast Cancer and the Wellcome Trust.
In the Section of Structural Biology
