Understanding the Selectivity of Genistein for Human Estrogen Receptor-β Using X-Ray Crystallography and Computational Methods

• Published in: Structure (London) Vol. 12; no. 12; pp. 2197 - 2207
• Main Authors: Manas, Eric S., Xu, Zhang B., Unwalla, Rayomand J., Somers, William S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-12-2004
• Subjects: Computer Simulation; Crystallography, X-Ray; Estrogen Receptor beta - chemistry; Estrogen Receptor beta - metabolism; Genistein - chemistry; Genistein - metabolism; Humans; Models, Molecular; Protein Structure, Tertiary
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2004.09.015

We present X-ray crystallographic and molecular modeling studies of estrogen receptors-α and -β complexed with the estrogen receptor-β-selective phytoestrogen genistein, and coactivator-derived NR box peptides containing an LXXLL motif. We demonstrate that the ligand binding mode is essentially identical when genistein is bound to both isoforms, despite the considerably weaker affinity of this ligand for estrogen receptor-α. In addition, we examine subtle differences between binding site residues, providing an explanation for why genistein is modestly selective for the β isoform. To this end, we also present the results of quantum chemical studies and thermodynamic arguments that yield insight to the nature of the interactions leading to estrogen receptor-β selectivity. The importance of our analysis to structure-based drug design is discussed.