3D models of human ERα and ERβ complexed with 5-androsten-3β,17β-diol.

Recently, binding of 5-androsten-3 beta,17 beta-diol (Delta(5)-androstenediol) to human estrogen receptor-beta (ERB) was found to repress microglia-mediated inflammation, which is associated with various neurodegenerative diseases, such as multiple sclerosis. In contrast, binding of estradiol to ER beta resulted in little or no repression of microglia-mediated inflammation. Binding of Delta(5)-androstenediol to ER beta, as well as to ER alpha, is unexpected because unlike estradiol, Delta(5)-androstenediol has a saturated A ring and a C19 methyl group. To begin to elucidate the interaction of Delta(5)-androstenediol with both ERs, we constructed 3D models of Delta(5)-androstenediol with human ER alpha and ER beta for comparison with the crystal structures of estradiol in ER alpha and ER beta. Conformational flexibility in human ER alpha and ER beta accommodates the C19 methyl on Delta(5)-androstenediol. This conformational flexibility may be relevant for binding of other Delta(5)-steroids with C19 methyl substituents, such as 25-hydroxycholesterol and 27-hydroxycholesterol, to ERs. (C) 2012 Elsevier Inc. All rights reserved.