Monomeric modeling of ERα LBD. The LBD (a) is a three-dimensional configuration composed of three folded strata. The central core is comprised of helices 5, 6, 9, and 10, which is positioned between two layers, one composed of helices 1–4; the other helices 7, 8, and 11. The size of the binding cavity is approximately two-fold greater than the molecular volume of estradiol. E2 binds diagonally (b) between helices 11, 6, and 3 and induces a conformational change in the LBD. Devoid of contact with the ligand, helix 12 (in red) is repositioned, thus providing a protective seal over the binding cavity. Reorientation of helix 12 in this manner intrinsically generates AF2, recruits coactivators, and promotes transcription. However, when the receptor binds selective estrogen receptor modulator or SERM (c), the length of the SERMs side chain exceeds the confines of the binding cavity. As a result, helix 12 is misaligned over the binding pocket. Diffraction studies indicate helix 12 is rotated 130° toward the N terminus of the LBD.
