The evolution of progesterone receptor ligands

Background: Understanding the molecular basis for the mixed profiles of progesterone receptor (PR) ligands will benefit future drug design. Results: Two differing mechanisms for the induction of mixed profiles by 11␤-steroids are described. Conclusion: Subtle electrostatic and steric factors explain the differing PR activities of 11␤-steroids. Significance: These observations will impact future drug-design strategies for PR and potentially other nuclear receptors.

Section: Modulation Of the Progesterone Receptor (Pr)mentioning

confidence: 99%

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

Lusher

Raaijmakers

Vu-Pham

et al. 2012

“…This makes them attractive pharmaceutical targets. Although SRs show exquisite selectivity for their endogenous hormones, SR-targeting drugs tend to be promiscuous and cause many off-target side effects (10,11). This is because SRs, consisting of the estrogen receptor, progesterone receptor (PR), androgen receptor (AR), mineralocorticoid receptor (MR), and glucocorticoid receptor (GR), descended from a common ancestor Ͼ500 million years ago (see Fig.…”

mentioning

confidence: 99%

Deciphering Modern Glucocorticoid Cross-pharmacology Using Ancestral Corticosteroid Receptors

Kohn

Deshpande

Ortlund

2012

Background: Drugs that target steroid receptors are notoriously promiscuous, causing an array of off-target side effects. Results: Reversal of the historical mutation H853R in the mineralocorticoid receptor (MR) fully restores agonist activity by mometasone furoate, an MR antagonist. Conclusion: A single residue outside of the ligand-binding pocket toggles agonism versus antagonism response by MR to synthetic ligands. Significance: Ancestral proteins are ideal tools to elucidate the mechanisms of drug selectivity.

“…Clashes between Met 909 and ligands are likely to destabilize helix-12 (21), which results in a reduced agonistic response. It has even been suggested that the degree of clash with Met 909 might correspond directly to the reduction in agonism (2), but this has yet to be shown categorically.…”

mentioning

confidence: 99%

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

Lusher¹,

Raaijmakers²,

Vu-Pham³

et al. 2011

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.