Wednesday, November 9, 2011

Enzyme 3D model provides basis for new drugs

A detailed model of an important enzyme in our body can aid us in the development of new drugs. An unprecedented high resolution picture shows individual atoms of a member of the MAP kinase family: enzymes that play an important role in cascaded signals that are sent throughout a cell, and regulate various cellular functions. They also play a role in disease, but because there are many MAP kinases with related structures, it is not easy to develop a drug that only inhibits one of them. Therefore, most drugs recognize multiple MAP kinases, which causes side-effects. Because of the stunningly high resolution of the investigated enzyme, researchers have found a seemingly unique area on a MAP kinase complex, which can possibly be used for the development of specific drugs.
The area has been dubbed KIS, and was found on the MAP kinase P38α which uses it to bind to specific peptides. It is likely that when the complex formation is blocked, the signalling pathway that it is part of will consequently be blocked as well. That means that a drug that binds to KIS would render MAP kinase signalling unable to activate its substrate and let the signal pass along the pathway.

Cells use P38 signalling after receiving stress cues, such as ultraviolet light, heat shock, and osmotic shock. The aim of the signalling pathway is to influence cellular growth and apoptosis. The complete pathway, however, is incredibly complex, and depends on a lot of other factors. It is important to find out how the KIS domain relates to MAP kinase signalling, and the corresponding effect it has on the cell. This proof of principle does show, however, that 3D modelling of enzymes could be a potent tool to discover unique structures that can be used to create more specific drugs, to reduce side-effects.

MAP kinase signalling has been found to play a role in the development of alzheimer's disease and cancer, among others. Because these enzymes function in almost all cells of our bodies, it is likely that the development of specific drugs will have an impact on the progress of disease. Currently, there are already P38 inhibitors in clinical trials, to investigate whether they can be used to treat autoimmune and inflammatory diseases. These drugs make use of previously discovered, but common, structures on the MAP kinase to recognize their target.
An overview of the MAP kinase signalling pathway. Each shape represents an enzyme.

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