Many current, best-selling drugs work by binding to G-protein-coupled transmembrane receptors in the place of ligands on the outside of cells. A successful drug will either shut down or turn up the function of the GPCR as compared to its natural binding partner, whatever is called for to solve the problem. Dr. Smrcka's team has been asking the question: what if, along with current drugs that interfere with disease on the outside of a cell membrane, we could also design drugs that interfere with the same pathway later in the process, when the disease-causing signal has passed from ligand to GPCR to the G protein subunit to enzymes within the cell?
Medical center researchers have been studying G proteins since 1994 because they exert control over so many proteins in so many cell types. Early tests revealed the existence of one location on the beta-gamma subunit in particular, a flexible "hotspot" where the majority of the subunit's interactions with enzymes take place. Past studies have mapped the surface of the G protein, but medical center researchers were the first to conceive that it includes a hotspot, a multi-purpose binding site, for protein-protein interaction. Such a hotspot would represent a crucial new target for anyone trying to manipulate the G protein subunit to fight disease.
In the current study, researchers had to first solve the structure of the hotspot before they could apply software to screen through databases of "drug-like molecules" to identify those that fit into, and bound tightly to, specific parts of the hotspot. These "drug-like" molecules could then be used to make precision changes in the hotspot's behavior. Any new drug would need to be able to block certain functions of the hotspot, while leaving the others in place. It would also have to be small
Contact: Greg Williams
University of Rochester Medical Center