Three-Dimensional Models of Estrogen Receptor Ligand Binding Domain Complexes, Based on Related Crystal Structures and Mutational and Structure−Activity Relationship Data

Abstract

On the basis of the recently determined crystal structures of the ligand binding domains (LBDs) of the retinoic acid nuclear receptors (NRs), we present a three-dimensional (3D) molecular model of the human estrogen receptor alpha (hERalpha) LBD. A literature search for mutants affecting the binding properties has been performed; 45 out of 48 published mutants can be explained satisfactorily on the basis of the model. Estradiol has been docked into the binding pocket to probe its interactions with the protein. Energy minimizations and molecular dynamics calculations were performed for various ligand orientations. To evaluate their quality, the different models were scored using known structure-activity relationship (SAR) data for selected close estradiol homologues. The two best models explain largely the binding affinities of more distantly related ligands.

Interactions of synthetic estrogens with human estrogen receptors

“…At the other end of the molecule the 17 -hydroxyl group of the D-ring makes a single hydrogen bond with the -nitrogen of His524 in helix H11. Additional stability of this hydrogen-bonding network is provided via salt bridge interactions between Glu353 and Arg394 (helix H5), and Glu419 and Lys531/ Asn532 (Tanenbaum et al 1998, Wurtz et al 1998. Arg394 is also involved in the orientation of the hormone in the LBD; the side chain of this residue is braced by a hydrogen bond to the carbonyl group of the residue preceding Phe404, which is fixed by its van der Waals' contact to ring A of the E 2 .…”

Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling

“…Perhaps the most important information has come from crystallographic studies of the ER binding domain complexed with different ligands (Brzozowski et al, 1997;Pike et al, 1999;Shiau et al, 2002). Several laboratories have used these data to describe conceptually similar models of ER function when liganded with either agonists or antagonists (Wurtz et al, 1998;Pike et al, 1999;Liu et al, 2002a, Shiau et al, 2002. The major limitations of such studies are the use of only the ligand binding domain (requires the assumption that no other domains of the ER affect its structure) and the use of crystal structures that may or may not fully reflect receptor structure in the more complex environment of a living cell.…”

Nitric Oxide Inhibits Selectively the 17β-Estradiol-Induced Gene Expression without Affecting Nongenomic Events in HeLa Cells

“…The ligandbinding domain and the DNA-binding domain of ER␣ contain four and nine Cys residues, respectively (16,17,38). Although the Cys residues present in the ligand-binding domain (Cys381, Cys417, Cys447, and Cys530) are solvent exposed, they are unlikely to undergo NO-mediated chemical modification(s).…”