Homology model for the ligand-binding domain of the human estrogen receptor

We have modeled the ligand-binding domain (LBD) of the human estrogen receptor protein (hER) by homology to the known crystal structure of the LED of the alpha isoform of human retinoate-X receptor (hRX). Alignment of hER with members of the nuclear receptor superfamily defined probable secondary structures which we used to constrain backbone torsion angles and hydrogen bonds. From published studies we identified key interactions between hER and estradiol to use to dock the hormone in its ligand-binding pocket. Since the hRX crystal structure corresponds to the unliganded form of the LED, we adopted the "mousetrap" mechanism proposed by Renaud et al, to predict the structure of the E-2-bound hER. Refinement by molecular dynamics and energy minimization gave a model which matches well the known facts about the estradiol phamacophore. It also provides a possible explanation for how hER discriminates between estradiol and testosterone.