title: The stereochemical complementarity of DNA and reproductive steroid hormones correlates with biological activity.
abstract: Modeling studies revealed that progesterone, testosterone, and estradiol are stereochemically complementary to the cavity formed between base pairs in the DNA sequence, 5'-dTdG-3' X 5'-dCdA-3'. Each steroid aligned precisely with the topography of the cavity and formed 2 stereospecific hydrogen bonds linking phosphate oxygens on adjacent DNA strands. Hydrogen bonding donor-acceptor relationships were different for each hormone. The remarkable stereochemical specificity of the hormone-DNA complexes was demonstrated by the lack of complementarity of steroid enantiomers and steroid analogs having alternate ring systems and/or changes in the position of functional groups. Fit of molecules into DNA in the manner of the parent hormone correlated with biological activity. Antagonists also fit into the cavity but differed from agonists in their hydrogen bonding linkages to DNA and/or extended out of the cavity beyond the helix. Unlike flat intercalating agents which form stable complexes with DNA, wedge shaped steroids may thus be capable of forming reversible sequence-specific complexes with DNA. We conclude that the stereochemistry of DNA can be used to predict hormonal activity.
mesh_terms: D000818:Animals; D001482:Base Composition; D001483:Base Sequence; D001665:Binding Sites; D004247:DNA / Q000032:analysis*; D004958:Estradiol / Q000378:metabolism; D006801:Humans; D008957:Models, Genetic; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D011944:Receptors, Androgen; D011959:Receptors, Estradiol / Q000235:genetics* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics*; D011980:Receptors, Progesterone / Q000235:genetics* / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism
chemical_list: D011944:Receptors, Androgen; D011959:Receptors, Estradiol; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D011987:Receptors, Steroid; D013739:Testosterone; D004958:Estradiol; D004247:DNA