Structural Basis for Agonism and Antagonism for a Set of Chemically Related Progesterone Receptor Modulators

Abstract

The progesterone receptor is able to bind to a large number and variety of ligands that elicit a broad range of transcriptional responses ranging from full agonism to full antagonism and numerous mixed profiles inbetween. We describe here two new progesterone receptor ligand binding domain x-ray structures bound to compounds from a structurally related but functionally divergent series, which show different binding modes corresponding to their agonistic or antagonistic nature. In addition, we present a third progesterone receptor ligand binding domain dimer bound to an agonist in monomer A and an antagonist in monomer B, which display binding modes in agreement with the earlier observation that agonists and antagonists from this series adopt different binding modes.

Androgen receptor antagonists for prostate cancer therapy

“…This specific position of helix 12 is required and can only be induced by agonists. When antagonists bind, they induce a distinct inactive LBD conformation in which helix 12 is repositioned from its active position or helix 12 is forced into a flexible position (Kauppi et al 2003, Hodgson et al 2008, Lusher et al 2011. This disables the binding of coactivators and/or enables the formation of another platform to which corepressors can bind.…”

X-ray Structures of Progesterone Receptor Ligand Binding Domain in Its Agonist State Reveal Differing Mechanisms for Mixed Profiles of 11β-Substituted Steroids

“…1). OrgA is a member of a compound class described as glucocorticoid receptor antagonists (28) but is a relatively potent PR partial agonist whose activity is described in a recent article (26). Bacteria were lysed in buffer A (50 mM Tris, pH 7.8, 250 mM NaCl, 10% glycerol, 10 mM ␤-mercaptoethanol) with 0.4 mM Pefablock (Roche Applied Science) and 50 M OrgA and purified on nickel nitrilotriacetic acid.…”

“…The ability of the PR-Asoprisnil complex to recruit co-activators indicates the agonist conformation of the receptor bound to Asoprisnil is both viable and biologically meaningful. This conclusion led us to utilize our previously described PR soaking method (16,26) to study Asoprisnil bound to a fixed agonistic conformation of PR to determine whether this structure would give additional insight into the molecular basis for Asoprisnil retained agonism compared with RU486.…”

“…1), we have used a previously described soaking technique (16,26) to determine the x-ray structure of the PR-Asoprisnil complex in its agonist state. This has allowed us to identify an interaction between the 11␤-benzaldoxime of Asoprisnil and Glu 723 that helps partially stabilize helix-12 in its agonist conformation.…”

Drug Design Approaches to Manipulate the Agonist-Antagonist Equilibrium in Steroid Receptors

“…A recent X-ray structure publication from our group suggests that PR antagonism seen in a compound series can in part be explained by a loss of these same interactions (Lusher et al, 2011). …”