3D models of human ERα and ERβ complexed with coumestrol

Coumestrol, a phytoestrogen found in alfalfa, clover, and beans, has nM affinity for both estrogen receptor-alpha [ER alpha] and ER beta. Recently, a novel activity of coumestrol was reported: coumestrol binding to human ER beta represses microglia-mediated inflammation, which is associated with various neurodegenerative diseases, such as multiple sclerosis. In contrast, estradiol binding to ER beta had little or no effect on repression of microglia-mediated inflammation. Coumestrol and estradiol have several structural differences, which suggest that each ligand could induce different conformations in ER beta and, thus, different transcriptional responses in brain microglia. To begin to understand how coumestrol binds to ER beta and ER alpha, we constructed 3D models of coumestrol with human ER beta and ER alpha, which were compared to the structures of these ERs with estradiol. Of four possible orientations of coumestrol in ER alpha and ER beta, one orientation had the most favorable contacts with both ERs. Other phytochemicals may activate ER beta and inhibit inflammation in brain microglia and be useful therapeutics for inflammatory conditions in the brain. (C) 2013 Elsevier Inc. All rights reserved.