Different ligands-different receptor conformations: Modeling of the hER alpha LBD in complex with agonists and antagonists

The aim of this study is to compare crystal structures of nuclear receptor ligand binding domains in complex with different agonists and partial agoni sts to achieve a better understanding of the three-dimensional structures a nd their ligand-induced conformational changes. This led to the identificat ion of structurally conserved "rigid" regions and more flexible parts of th e proteins. The analysis was found to be of great value in fitting selected non-steroidal compounds into the human estrogen receptor alpha (hER alpha) ligand binding pocket. The experimentally determined binding affinities fo r a number of 2-aryl indoles and 2-aryl indenones are in good agreement wit h the subsequently modeled binding interactions. To date, no crystal struct ure is published for a complex with a pure antagonist. We therefore used th e available structural information on complexes with partial agonists and t he crystal structure of a mutant protein in complex with estradiol displayi ng a similar conformation to predict binding interactions for antagonists. The results are discussed in detail. (C) 2001 John Wiley & Sons, Inc.