A putative step in steroid hormone action involves insertion of steroid ligands into DNA facilitated by receptor...

The hypothesis is advanced that hormonal ligands in the steroid/thyroid superfamily act through insertion between base pairs in partially unwound DNA. Using published X-ray coordinates of the complex of the glucocorticoid hormone response element (GRE) with the glucocorticoid receptor DNA binding domain, the interface between the protein and the gene was examined. The site 5'-TG-3'-5'-CA-3' previously shown to accommodate cortisol was found in the first two bases of the GRE half sites, 5'-TGTTCT-3'. These base pairs were sufficiently exposed at the receptor-gene interface to permit access by the steroid. Docking of cortisol into the receptor/DNA complex resulted in a favorable van der Waals energy. Given the general lack of correlation of receptor binding with hormonal activity, we propose that hormone action involves an additional step in which the receptor protein in concert with other transcription factors inserts the hormone into the DNA. This notion provides an explanation for earlier paradoxical observations including structural analogies between base pairs and steroid hormones. The insertion hypothesis suggests that receptor bound ligand facilitates DNA unwinding, stereospecific control of donor/acceptor functional groups on the DNA followed by insertion and release of the ligand between base pairs at 5'-TG-3'-5'-CA-3'.