A molecular recognition hypothesis for nonpeptides: Na(+)K(+)ATPase and endogenous digitalis-like peptides

The molecular recognition hypothesis for peptides is that binding sites of ligands and their receptors are encoded by short, complementary segments of DNA. A corollary hypothesis for nonpeptide ligands posited here is that pe ptide replicas may be encoded by the DNA segment complementary to the recep tor binding sites for nonpeptides. This corollary was tested for digitalis, a family of cardiotonic and natriuretic steroids including ouabain. A hexa peptide (ouabain-like peptide, OLP) complementary to a ouabain binding site on sodium/potassium dependent adenosine triphosphatase (Na(+)K(+)ATPase) e xhibited activity in a digitalis bioassay. Antisera to the complementary pe ptide (OLP) stained the neurohypophysis in an immunocytochemical procedure. The complementary peptide was found to share an identical 4-amino acid reg ion with the 39-amino acid glycopeptide moiety of the vasopressin-neurophys in precursor. This glycopeptide was isolated from pituitary extracts; it ex hibited digitalis-like activity in the submicromolar range and cross-reacte d with complementary peptide antibodies. Another digitalis-like substance w ith high activity also was detected in the extracts. These results demonstr ate that the vasopressin-neurophysin glycopeptide has digitalis-like activi ty. Moreover, the findings are consistent with the hypothesis that peptide mimetics of nonpeptides are encoded in the genome.