Abstract
Domain swapping continues to be the most successful area of protein engineering. Complementary structural and functional information is now beginning to emerge from studies that aim to redesign dehydrogenases, proteases and metal-binding sites. One important conclusion from this work is that residues that do not contact the substrates can be important determinants of substrate specificity. These studies suggest an intriguing possibility: new enzymes may be more successfully engineered by selecting first for catalysis, then optimizing substrate binding, instead of attempting to adapt binding sites for catalysis.