Ph.D., University of California - San Diego (1972)
B.A., University of Minnesota (1967)

Postdoctorate, MRC Laboratory of Molecular Biology, Cambridge (1972-74)

Research Interests

Biochemistry: Structural Biology, Protein Engineering, And Drug Design

My research group is interested in the structure, action and engineering of biologically important proteins, and in the rational design of therapeutic agents. A linchpin of our work is the determination of protein structure by the powerful method of X-ray crystallography. This allows us to see proteins at the atomic level, and in particular to see which amino acids contribute to the substrate binding and catalytic site of a given enzyme. It is often possible to bind substrate analogs to the enzyme and see how the two interact. With the three-dimensional model in hand we can hypothesize about its mechanism of action. To test our hypothesis about the mode of action we often clone the gene coding for the protein and express it in bacteria, in high yield. We then use the method of site-directed gene mutagenesis to specifically change key amino acids to other residues and measure the effect on protein activity. In this way we can determine if a given amino acid is crucial, important or generally irrelevant to the action of the protein. Besides using the protein model to guide genetic engineering work, we also use it to aid in the rational design of drugs. Many of the proteins we study are important to pathogenesis and inhibitors can be thought of as therapeutic drugs.