University of Manchester scientists have uncovered the 3D structure of Mps1 - a protein that regulates the number of chromosomes during cell division and thus has an essential role in the prevention of cancer - which will lead to the design of safer and more effective therapies.
Mps1 belongs to the family of proteins called kinases. When subsets of these enzymes become deregulated, cancer can be one of the outcomes - making them a critical target for research by oncologists. Over 100 of the 500 or so kinases have been shown to be associated with cancer, but so far scientists only know the 3D structure of a handful. Knowing the structure is critical for the design of new kinase inhibitors as therapeutic agents, an area of enormous importance to the pharmaceutical industry. Over 100 kinase inhibitors are currently in clinical trials, and the revolutionary kinase inhibitor Glivec was approved for treating Leukaemia in the UK in 2001.
Mps1 is particularly important as it controls a 'checkpoint' that cells use to encourage accurate chromosome sorting during mitosis. Mps1 therefore prevents aneuploidy, the change in the number of chromosomes that is closely associated with cancer.
Dr Patrick Eyers and his team, including Hong Kong-born PhD student Matthew Chu, used the Diamond Light synchrotron, a "super-microscope" that works by speeding electrons around a huge doughnut-shaped chamber the size of five football pitches until they are travelling so fast they emit high energy particles. The X-rays were "fired" at a pure sample of the protein, allowing the researchers to "see" the protein's atomic structure for the first time.
Their structure revealed the pocket where Mps1 binds to ATP, the natural substrate from which Mps1 transfers a phosphate group to its cellular target proteins. Further work showed the protein in complex with the ATP-competitive inhibitor SP600125, a well-known but non-specific inhibitor of many kinases, which revealed a secondary pocket not utilised by this compound. If a next-generation drug can be designed to specifically block this secondary pocket, it is hoped that Mps1 will be specifically disabled, killing rapidly dividing cells such as those found in tumours.