TRABITA Protein Models Under Investigation

Within TRABITA four different protein models are under investigation which are known to have transient binding pockets. With aid of these models potential solutions to find transient binding pockets can be validated.

B1 Hausch: FKBPs

The immunophilin FKBP5 is an established risk factor for stress-associated diseases like depression, for obesity and diabetes, and for chronic pain. It is essential to pharmacologically distinguish between FKBP51 and FKBP52 which is structurally alike but plays a vital role in the human body. For only targeting FKBP51 the work group of Prof. Hausch developed a drug that affects a transient binding pocket of FKBP51.

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B2 Meyer-Almes: HDAC

The work group of Prof. Meyer-Almes works on modulation of the protein HDAC, which is of pivotal importance in Chorea Huntington pathogenesis and a variety of cancer diseases. Drugs targeting HDAC and their binding kinetics will be investigated by specific assays to uncover ligands with special binding modes on the one hand and transient binding pockets on the other.

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B3 Steinhilber: 5-LO

5-Lipoxygenase (5-LO) catalyzes the biosynthesis of Leucotrienes from Arachidonic acid. Leukotrienes mediate inflammatory and allergic reactions. Novel information gives rise to the conjecture, that 5-LO influences other signaling proteins as well as miRNA biosynthesis. Furthermore, 5-LO can be steered via transient binding pockets. The work group of Prof. Steinhilber is responsible for the identification of new transient binding pockets within the TRABITA project.

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B4 Knapp: Kinases

One of the largest protein families is formed by Kinases which facilitate signal transduction in cells by phosphorylation and their disruption causes diseases marking their importance as a drug target. However, it is complicated to develop selective inhibitors due to the dimension of the kinase family and their mutual ATP binding site. One silver lining are allosteric inhibitors, which circumvent the ATP sites and are highly selective. A fragment library of allosteric inhibitors to be validated by biophysical methods was set up by Prof. Knapp and his coworkers.

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