**3.4 Reduce the stabilizing interactions between the ligand and helix-12 3.4.1 Case study: the estrogen receptors alpha & beta**

Methods for antagonizing or reducing the agonism of steroid receptors that do not involve direct steric clashes with the receptor are often referred to as "passive antagonism". This term was coined by the group of Geoffrey Greene to explain their observations when studying the binding of tetrahydrochyrsene (THC) and its interactions with ERα and ERβ (Shiau et al, 2002).

THC is an ERα agonist and an ERβ antagonist. The group of Greene was able to conclude, after generating X-ray structures of both complexes that THC stabilizes ERα in its agonist conformation but ERβ is in an antagonist conformation. This difference on its own is of significant interest, but the study also demonstrated that the reason for ERβ not adopting an agonist conformation was due to missing stabilizing interactions between the receptor and the ligand. They observe that in ERβ residues Leu476 and Met479 are not positioned correctly by the ligand to form interactions with relevant residues in helix-12 to stabilize its agonist conformation. The result is a failure of THC to stabilize the agonist conformation of helix-12 and therefore a shift in the agonist-antagonist equilibrium. The fact that THC has such differing effects on two such similar receptors illustrates the challenge when following this or any of the five described approaches in drug-design.
