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

Recently, binding of 5-androsten-3β,17β-diol (Δ5-androstenediol) to human estrogen receptor-beta (ERβ) was found to repress microglia-mediated inflammation, which is associated with various neurodegenerative diseases, such as multiple sclerosis. In contrast, binding of estradiol to ERβ resulted in little or no repression of microglia-mediated inflammation. Binding of Δ5-androstenediol to ERβ, as well as to ERα, is unexpected because unlike estradiol, Δ5-androstenediol has a saturated A ring and a C19 methyl group. To begin to elucidate the interaction of Δ5-androstenediol with both ERs, we constructed 3D models of Δ5-androstenediol with human ERα and ERβ for comparison with the crystal structures of estradiol in ERα and ERβ. Conformational flexibility in human ERα and ERβ accommodates the C19 methyl on Δ5-androstenediol. This conformational flexibility may be relevant for binding of other Δ5-steroids with C19 methyl substituents, such as 25-hydroxycholesterol and 27-hydroxycholesterol, to ERs.

► We constructed a 3D model of Δ5-Adiol in human ERα and ERβ.
► The C19 methyl group of Δ5-Adiol fits in ERα and ERβ.
► Other Δ5-steroids may be transcriptional activators of ERα and ERβ.