Structures important in mammalian 11 beta- and 17 beta-hydroxysteroid dehydrogenases

We have used the X-ray crystallographic structures of rat and human dihydropteridine reductase and Streptomyces hydrogenans 20 beta-hydroxysteroid dehydrogenase to model parts of the 3-dimensional structure of human 11 beta- and 17 beta-hydroxysteroid dehydrogenases. We use this information along with previous results from studies of Drosophila alcohol dehydrogenase mutants to analyze the structures in binding sites for NAD(H) and NADP(H) in 11 beta-hydroxysteroid dehydrogenase-types 1 and 2. We also examine the structure of an alpha-helix at catalytic site of 17 beta-hydroxysteroid dehydrogenase-types 1, 2, 3, and 4. This alpha-helix contains a highly conserved tyrosine and lysine. Adjacent to the carboxyl side of this lysine is a site proposed to be important in subunit association. We find that 11 beta- and 17 beta-hydroxysteroid dehydrogenases-type 1 have the same residues at the ''anchor site'' and conserve other stabilizing features, despite only 20% sequence identity between their entire sequences. Similar conservation of stabilizing structures is found in the 11 beta- and 17 beta-hydroxysteroid dehydrogenases-type 2. We suggest that interactions of the dimerization surface of alpha-helix F with proteins or membranes may be important in regulating activity of hydroxysteroid dehydrogenases.