Adenylyl Cyclases

We have identified MANT-substituted nucleotides as novel class of highly potent and selective AC inhibitors. In collaboration with Dr. S. Sprang (Dept. of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA), we have solved the crystal structure of a MANT-nucleotide/AC complex and studied the kinetics of AC assembly by fluorescence spectroscopy. These studies will be extended to other fluorescent nucleotides such as TNP-nucleotides and other AC isoforms. Much effort will be devoted to the development of isoform-selective AC inhibitors (collaboration with Prof. König). Those studies will be supported by molecular modeling studies (collaboration with Dr. G. Lushington, KU). Our long-term goal will be the development of cell-permeable AC inhibitors. The analysis of AC inhibitors in cardiomyocytes is conducted in collaboration with Prof. S. Herzig (Department of Pharmacology, University of Cologne). For the analysis of AC isoform functions in the kidney, Prof. Kurtz will be our collaboration partner. Moreover, we will analyze the interactions of forskolin-derived diterpens with AC and search for endogenous ligands of the forskolin binding site. Furthermore, we will address the issue of homo- and heterodimerization of AC molecules for their function. Finally, we will study the regulation and inhibition of bacterial ACs such as the AC toxins from B. pertussis and B. anthracis. Those studies will be conducted in cooperation with Dr. W.-J. Tang (University of Chicago, IL, USA).