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A new mechanism for reversible proteasome inhibition
Date:12/13/2010

. While healthy cells survive by building up a new proteasome, the fast-growing cancer cells suffocate in their own waste and end up in apoptosis.

The trick of both of these proteasome blockers is a two-step reaction. The tiny molecule fits a specific site on the proteasome like a key going into a lock. However, the reversible docking at the binding site is followed by an irreversible ring formation that prevents the key from being pulled back out. By choosing another head group, Professor Michael Groll und Dr. Melissa Graewert were able to achieve a reversible ring formation. The new head group contains an aldehyde and a keto group in immediate proximity. They also react with the binding sites on the proteasome by forming a ring. However, the reaction of these two groups is reversible: The key can be removed from the lock and the proteasome can resume its work.

Within the framework of their work supported by the Cluster of Excellence Center for Integrated Protein Science Munich (CIPSM), the TUM scientists succeeded in confirming the assumed mechanism using X-ray structure analysis of inhibited proteasome crystals. It also became clear how this binding mechanism could be developed into a drug with fewer side effects. In addition to the head group, the binding mechanism contains a short chain of amino acids that can be designed to fit into the binding pockets of the proteasome. By varying the amino acids, the binding can be optimized to specifically attack immuno-proteasomes.

"The reversible two-step binding mechanism shown here is unique to proteasomes," says Michael Groll, who holds the Chair of Biochemistry at the Department of Chemistry of the Technische Universitaet Mnchen. "This explains the high selectivity and leads us to expect relatively minor side effects. The reversible reaction opens up a much wider field of application. We can now develop these binding mechanisms further in the direction of immunosuppressive agents." It is pre
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Contact: Andreas Battenberg
battenberg@zv.tum.de
49-892-891-0510
Technische Universitaet Muenchen
Source:Eurekalert  

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