Researchers at Manchester have identified a potential target for the development of new therapies to treat and prevent cancer.
They 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.
AdvertisementMps1 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.
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 colleagues 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.
Researchers suggest that 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.
The research team hopes that their finding will allow chemists to design an anti-cancer drug with fewer side effects, allowing scientists to assess the relative importance of Mps1 inhibition in different disease indications, including those that are currently hard to treat such as lung and pancreatic cancers.
The study is published in the Journal of Biological Chemistry.
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