Three-dimensional structures of steroids and their protein targets

Abstract

Steroid receptors and enzymes that control steroid synthesis and metabolism work together to control vital hormonal functions. Crystallographic data on steroids having high affinity for estrogen, progestin, and corticoid receptors suggest that receptor binding is primarily the result of a high level of complementarity between the receptor and the steroidal A-ring. The crystal structures of two steroid dehydrogenase enzymes reveal the location of the active site, the position of the conserved catalytic triad (Tyr-Lys-Ser), a possible mechanism of keto-hydroxyl interconversion and the basis for selectivity. A complex between carbenoxolone and one of the enzymes reveals how the active ingredient in licorice inhibits this enzyme as well as human 11β-hydroxysteroid dehydrogenase (11β-HSD). The complex reveals that the inhibitor fills the substrate binding pocket, displaces the cofactor and accepts a hydrogen bond from a tyrosine residue, one of less than 20 strictly conserved residues in the family of enzymes, explaining how ingestion of licorice can produce hypertension.