We believe that steroid binding is not required for receptor binding to DNA, but instead induces a conformational change in the receptor domains involved in the protein-protein interactions proposed above. Data from Hansen and Gorski (1986), and more recent studies (M. Fritsch and J. Gorski, unpublished results) strongly suggest that the steroid binding domain when bound to estrogens undergoes a dramatic change in conformation characterized by a loss of hydrophobic surface. This marked change in the steroid binding domain probably affects the so-called dimerization region located in this domain and thus the interaction of receptor with nuclear proteins in vivo. In our working model, ER is bound to specific DNA sequences or response elements of a variety of genes with or without estrogen. Ligand binding induces conformational changes in the steroid binding and perhaps other domains of the receptor that in turn change receptor interaction with the transcriptional machinery. The nature of this change is not at all clear at present, and the possibility of enzymatic modification of receptor or associated transcription factors should not be excluded. Whatever the mechanism of receptor action on transcription, we expect it kinetically will be closely related to the occupancy of the receptor with estrogen. Finally, any model of ER interactions with target genes also needs to account for the drastic ligand effect on the extractability of all ER from the nucleus.