The positioning of helix 12 is directed by effects on the secondary and tertiary structure of the LBD programmed by ligand binding. Agonists stabilize secondary structural elements, extending the lengths of helices 3,8 and 11. This then shortens the loop between helices 11 and 12, which in turn does not allow helix 12 to fit in the hydrophobic coactivator pocket. The precise geometry of the ligand and its interactions with different regions of LBD lead to a differential stabilization of either the agonist or antagonist conformations. Current studies focus on understanding the mechanism by which ligands determine these structural changes.
Unfolded conformations are more stable than the native state of alpha-lytic protease.