Different ligands–different receptor conformations: Modeling of the hERα LBD in complex with agonists and antagonists

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Abstract
The aim of this study is to compare crystal structures of nuclear receptor ligand binding domains in complex with different agonists and partial agonists to achieve a better understanding of the three‐dimensional structures and their ligand‐induced conformational changes. This led to the identification of structurally conserved “rigid” regions and more flexible parts of the proteins. The analysis was found to be of great value in fitting selected non‐steroidal compounds into the human estrogen receptor alpha (hERα) ligand binding pocket. The experimentally determined binding affinities for a number of 2‐aryl indoles and 2‐aryl indenones are in good agreement with the subsequently modeled binding interactions. To date, no crystal structure is published for a complex with a pure antagonist. We therefore used the available structural information on complexes with partial agonists and the crystal structure of a mutant protein in complex with estradiol displaying a similar conformation to predict binding interactions for antagonists. The results are discussed in detail. © 2001 John Wiley & Sons, Inc. Med Res Rev, 21, No. 6, 523–539, 2001