Synchrotron Sheds Light on Possible Anticancer Target

The Diamond Light Synchrotron is a third generation, medium energy source, with electron beam energies of 3 GeV. Specially designed arrays of magnets, called insertion devices, produce exceptionally bright light beams to suit a huge variety of complex experiments. At the heart of the synchrotron is a storage ring: a huge, doughnut-shaped vacuum chamber. Electrons are accelerated by the linear accelerator and the booster synchrotron, and confined to travel around the storage ring at nearly the speed of light. Because the electrons are constantly changing direction, they are accelerating, and accelerating electrons lose energy in the form of synchrotron light.

In the current study, published in the August 1, 2008, edition of the Journal of Biological Chemistry (JBC), investigators at the University of Manchester (United Kingdom) used the Diamond Light Synchrotron to determine the X-ray structure of Mps1, both alone and in complex with the ATP competitive inhibitor SP600125.

Mps1 adopted a classic protein kinase fold, with the inhibitor sitting in the ATP-binding site where it was stabilized by hydrophobic interactions. In addition, they identified a secondary pocket, not utilized by SP600125, which might be exploited for the rational design of specific Mps1 inhibitors. These structures provide important insights into the interaction of this protein kinase with small molecules and suggest potential mechanisms for Mps1 regulation.

Co-senior author Dr. Patrick Eyers, professor of pharmaceutical sciences at the University of Manchester, explained, "Mps1 is a rational target because of its critical role in preventing aneuploidy. 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. The crystallographic structures of only a few key ‘mitotic' kinases are currently known so we are very early in the game. The scientific community has high hopes for developing novel ‘anti-mitotic' cancer therapies using this method of structure-based drug design.”

Related Links:
University of Manchester
Diamond Light Synchrotron