Industrial applications of enzymes are frequently limited by the availability of large quantities of soluble protein. We have developed a procedure for selecting soluble variants of an insoluble protein. The procedure utilises the enzyme DHFR that, as noted above, is inhibited by the antibiotic TMP. In our procedure, a mutant library of an insoluble target protein is fused to that of dihydrofolate reductase. Variants of the target protein that have enhanced solubility can be selected on the basis of their ability to overcome the normally lethal effects of TMP. This technique can be used to enhance the solubility of proteins for structural genomics studies. This technique has been applied to an insoluble metal binding domain of aminopeptidase P from E. coli. The results of this study have implications for the metal binding requirements of the protein.