Structural requirements for the binding of dexamethasone to nuclear envelopes and plasma membranes

The specificity of dexamethasone binding sites on nuclear envelopes (NE) and plasma membranes (PM) was determined in competition studies with natural and synthetic steroids. The binding affinities for nuclear envelopes and plasma membranes were then correlated with the three-dimensional structures of the ligands. Three major factors are implicated in the ability of the steroid to bind to the membrane sites: (1) the separation between the terminal oxygen atoms substituted at atoms C3 and C17, or attached to the substituent at C17, is found to be longer than 10 Å for the medium and high affinity steroids; (2) the β-orientation of the oxygen atom in the C17-substituent to the D-ring is favored over α-orientation; and (3) bulky substituents and nontypical configurations are not accepted by the binding sites. A nearly linear correlation between the O3...O (substituted at C17) distance and the binding affinity of the tested steroids is observed; explanations for the lack of linear correlation of some steroids are given. A preliminary model for the interaction of steroids with these membrane sites is proposed which requires two hydrogen bonding regions that interact with the 2 oxygen atoms and some steric restriction sites that prevent the binding of steroids with large substituents. The hydrophobicities of the steroids do not correlate with binding affinities to the dexamethasone binding sites; hydrophobicity seems to play a minor role in these steroid-membrane interactions. Comparisons of the specificity of the dexamethasone binding sites on membranes to the specificity of various steroid receptors are also presented.