3D mapping may provide key to cancer
EU-funded scientists have brought to light the three dimensional structure of a protein that is vital in preventing cancer. The protein in question, Mps1, plays an important role in regulating the number of chromosomes during cell division, and it is this function that makes it so important in the fight against cancer. The researchers, who are based at the University of Manchester in the UK, believe that their finding could lead to the development of new cancer therapies which are both safer and much more effective. Their results are published in the latest edition of the Journal of Biological Chemistry. Dr Lydia Tabernero, one of the co-authors of the study, was very pleased with the results they were able to obtain. 'This work presents the first crystallographic structure of human Mps1, an important regulator of chromosomal stability and a potential target in cancer therapy,' she commented. 'Our research has revealed several important structural features and additional binding sites that could be exploited for the development of specific Mps1 inhibitors.' Mps1 belongs to a group of proteins called the kinases. It is when subsets of these enzymes become deregulated that cancer occurs. Understanding how kinases work is crucial to combating cancer. Up until now, approximately 100 of the 500 kinases have been shown to be associated with cancer. Unfortunately, scientists have only been able to map the 3D structure of a mere handful. Knowing the structure is critical for the design of new kinase inhibitors as therapeutic agents. This is an area of enormous importance to the pharmaceutical industry. Currently over 100 kinase inhibitors are undergoing clinical trials. The reason why the group chose to study Mps1 is that it acts as a sort of 'checkpoint' that cells use to encourage accurate chromosome sorting during cell division. Mps1 therefore prevents aneuploidy, the change in the number of chromosomes that is closely associated with cancer. 'Mps1 is a rational target because of its critical role in preventing aneuploidy,' explained Dr Patrick Eyers of the University of Manchester, who lead the research. 'We wanted to see what this protein looked like at the molecular level and, by revealing the active site lock, help design a new inhibitory 'key' to physically block the ATP-binding site.' Dr Eyers and his team made use of the Diamond Light synchrotron for their research. This 'super-microscope' 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. In this manner researchers were able to 'see' the protein's atomic structure for the first time. 'The crystallalographic structures of only a few key mitotic kinases are currently known so we are very early in the game,' commented Dr Eyers. 'The scientific community has high hopes for developing novel 'anti-mitotic' cancer therapies using this method of structure-based drug design.' EU support for the study came from the PTPNET ('Protein tyrosine phosphatases: structure, regulation and biological function') project, which is financed by a Marie Curie Research Training Network grant from the EU's Sixth Framework Programme (FP6).
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