Figure 9: Proposed mechanisms for partial agonism of PR. Asoprisnil can switch between agonist and antagonist PR conformations, mediated by Glu723 positioning. A) PR-Asoprisnil in the agonist conformation (PDB 4A2J); the drug interacts with a hydrogen-bond network between Glu723 and Met908/Met909 backbone atoms, strengthening the network. B) PR-Asoprisnil in the antagonist conformation (PDB 2OVH); Glu723 is pointed away from the ligand, with no hydrogen bonds formed. C) In second mechanism, ligand activity is modulated by plasticity of Trp755. In the PR-Org3H agonist conformation (PDB 4APU), Trp755 is turned toward the ligand, different than conformation in PR-Asoprisnil complexes. The plasticity of this residue suggests that a larger pendant group could cause it to swing towards Val912, destabilizing H12.