Chapter XV Tracking Down a New Putative Drug Target for Osteoporosis: Structure of an Essential Region of the Proton Translocation Channel

In the last decades, osteoporosis has become a major subject in the field of drug discovery and design. One of the proteins recently considered relevant to use as a drug target is the membrane-bound enzyme H+-VO-ATPase. This proton pump is located in the osteoclast cells, which are positioned at the bone surface. In these cells the enzyme controls the proton flux to the bone and consequently bone resorption. One major task on drug design is the knowledge of the secondary and tertiary structure of the enzyme involved. The topology of the V-ATPase protein complex has been largely established, however, the three-dimensional structure is only known for some individual subunits. This chapter reviews our recently published work on the secondary and tertiary structure of the proton translocation channel located in subunit a of the V-ATPase complex. For this purpose, we designed two peptides consisting of 25 and 37 amino acid residues, representing the seventh transmembrane segment of subunit a, which encompass the proton translocation channel as well as the region of interest for interaction with possible inhibitors. Using a combination of NMR (nuclear magnetic resonance) and CD (circular dichroism) spectroscopy the structure of these V-ATPase peptides was studied in different membrane-mimicking environments. The results indicate that a primordial transmembrane segment of this protein region adopts an D-helical conformation and i