Lb. Hendry et al., THE LIGAND INSERTION HYPOTHESIS IN THE GENOMIC ACTION OF STEROID-HORMONES, Journal of steroid biochemistry and molecular biology, 65(1-6), 1998, pp. 75-89
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.