Our laboratory is interested in the structure and mechanism of the enzymes and molecular switches that carry out cellular signal transduction and DNA replication. We use x-ray crystallography to determine the three-dimensional structures of proteins involved in signaling and replication, as well as biochemical, biophysical, and computational analyses to figure out how they work. A major focus in the laboratory is understanding the allosteric mechanisms that enable proteins to be exquisitely sensitive to input signals. The major class of signaling molecules that we study are the protein kinases, a large family of closely related enzymes that catalyze the addition of phosphate to serine, threonine, and tyrosine residues in proteins. We also study the mechanism by which the guanine nucleotide-binding protein Ras, a crucial signaling switch, is activated by hormone and growth factor receptors. A new project (in collaboration with Michael Marletta, UC Berkeley) involves the analysis of the guanylyl cyclases, enzymes that generate cGMP, an important mediator of cell signaling. Because of the importance of these signaling molecules in cancer, much of our work has implications for the development of new drugs. We are also currently exploring the molecular mechanism of high-speed DNA replication.