Crystal structures of Helicobacter pylori type II dehydroquinase inhibitor complexes: new directions for inhibitor design.

The crystal structures of the type II dehydroquinase (DHQase) from Helicobacter pylori in complex with three competitive inhibitors have been determined. The inhibitors are the substrate analogue 2,3-anhydroquinate (FA1), citrate, and an oxoxanthene sulfonamide derivative (AH9095). Despite the very different chemical nature of the inhibitors, in each case the primary point of interaction with the enzyme is via the residues that bind the C1 functionalities of the substrate, 3-dehydroquinate, i.

Fluorescence properties of green fluorescent protein FRET pairs concatenated with the small G protein, Rac, and its interacting domain of the kinase, p21-activated kinase.

Many diseases are caused by aberrant cell signalling controlled by intracellular protein-protein interactions. Inhibitors of such interactions thus have enormous potential as chemotherapeutic agents. It is advantageous to test for such inhibitors using cell-based screens in which modulation of the interaction gives a rapid response.

Specificity of substrate recognition by type II dehydroquinases as revealed by binding of polyanions.

The interactions between the polyanionic ligands phosphate and sulphate and the type II dehydroquinases from Streptomyces coelicolor and Mycobacterium tuberculosis have been characterised using a combination of structural and kinetic methods. From both approaches, it is clear that interactions are more complex in the case of the latter enzyme. The data provide new insights into the differences between the two enzymes in terms of substrate recognition and catalytic efficiency and may also explain the relative potencies of rationally designed inhibitors.