Unnatural ligands for engineered proteins: New tools for chemical genetics

Small molecules that modulate the activity of biological signaling molecule s can be powerful probes of signal transduction pathways. Highly specific m olecules with high affinity are difficult to identify because of the conser ved nature of many protein active sites. A newly developed approach to disc overy of such small molecules that relies on protein engineering and chemic al synthesis has yielded powerful tools for the study of a wide variety of proteins involved in signal transduction (G-proteins, protein kinases, 7-tr ansmembrane receptors, nuclear hormone receptors, and others). Such chemica l genetic tools combine the advantages of traditional genetics and the unpa ralleled temporal control over protein function afforded by small molecule inhibitors/activators that act at diffusion controlled rates with targets.