THE LIGAND INSERTION HYPOTHESIS IN THE GENOMIC ACTION OF STEROID-HORMONES

Gene regulation by steroids is tightly coupled to hormone concentratio n and stereochemistry. A key step is binding of hormones to receptors which interact with consensus DNA sequences known as hormone response elements (HREs). The specificity and strength of hormone binding do no t correlate well with hormonal activity suggesting an additional step involving recognition of ligand by the gene. Stereospecific fit of hor mones between base pairs and correlation of fit with hormonal activity led to the proposal that such recognition involves insertion of hormo ne into DNA. Here, the feasibility of insertion was investigated using computer models of the glucocorticoid receptor DNA binding domain bou nd to its HRE. The site reported to accommodate glucocorticoids was fo und in the HRE and was exposed to permit unwinding at this locus. The resulting cavity in the unwound DNA/receptor interface fit cortisol re markably well; cortisol formed hydrogen bonds to both the receptor and DNA. Current experimental evidence is generally consistent with Ligan d binding domains of receptors undergoing a conformational change whic h facilitates transfer of the ligand into the unwound DNA/receptor int erface. We propose this step is rate limiting and alterations in recep tor, DNA or hormone which attenuate insertion impair hormonal regulati on of gene function. (C) 1998 Published by Elsevier Science Ltd. All r ights reserved.