PKB signalling protein unravelled

21 Jan 2009

First 3D movie of tumour protein gives new drug hope

Scientists have created the first complete model of a molecule which captains a key cell signalling network to prevent cancer – and exposed the secret of how a highly selective drug can intervene to control its activity, according to a study published in PLoS Biology today.

Scientists based at Cancer Research UK’s London Research Institute used a combination of an imaging technique and modelling to create a 3D interactive model of the enzyme protein kinase B (PKB), and observed how it functions in cells.

PKB is a chief regulator of the signalling pathways that control how cells behave. Disruption to this network is one route to cancer and excessive activation of PKB is observed in tumours. Understanding more about how PKB functions, will help scientists find out how existing drugs work to switch PKB off so that it behaves as it should in normal cells. This will help scientists develop more effective drugs to target PKB and knock out cancer.

The moving interactive model exposed a secret cavity in the enzyme’s structure which was shown by the scientists to be the point where it interacts with regulatory drugs. They demonstrated that an inhibitor molecule could bind to this cavity area to lock the enzyme into an inactive state.

Scientists already know that a family of ‘allosteric’ drugs can switch off this enzyme but until now no-one knew how they worked. Currently the drugs are not suitable for use in people. This discovery will pave the way to the development of similar drugs that are safe and effective in cancer patients.

Lead author, Professor Banafshe Larijani, head of the Cell Biophysics Laboratory at Cancer Research UK’s London Research Institute, said: “An overactive form of PKB is observed in tumours, so finding a way to switch this enzyme off lets us, in effect, put up road blocks along routes by which cancer can develop.

“Our team has deduced for the first time the model structure of this critical protein and how it interacts with other molecules in the cell. This means we now understand how existing drugs keep it in check, giving us the information we need to develop better ones.”

Dr Lesley Walker, director of cancer information at Cancer Research UK, said: “We have recognised the important role this protein can have in driving cancer development and now we know its full structure, the coast is clear to develop new therapies which will help in our fight to beat cancer.”

Article: Banafshe Larijani et al. Role of a Novel PH-Kinase Domain Interface in PKB/Akt Regulation: Structural Mechanism for Allosteric Inhibition. PLoS Biology 21 January 2009.