Crystal Structure of Human Estrogen-related Receptor α in Complex with a Synthetic Inverse Agonist Reveals Its Novel Molecular Mechanism

Abstract

(H12) has to move away, and thus the activation helix H12 is displaced from its agonist position. This is a novel mechanism of H12 inactivation, different from ERR␥, estrogen receptor (ER) ␣, and ER␤. H12 binds (with a surprising binding mode) in the coactivator groove of its ligand binding domain, at a similar place as a coactivator peptide. This is in contrast to ERR␥ but resembles the situation for ER␣ (raloxifene or 4-hydroxytamoxifen complexes). Our results explain the novel molecular mechanism of an inverse agonist for ERR␣ and provide the basis for rational drug design to obtain isotype-specific inverse agonists of this potential new drug target. Despite a practically filled LBP, the finding that a suitable ligand can induce an opening of the cavity also has broad implications for other orphan nuclear hormone receptors (e.g. the NGFI-B subfamily).

Double PHD Fingers Protein DPF2 Recognizes Acetylated Histones and Suppresses the Function of Estrogen-related Receptor α through Histone Deacetylase 1

“…Reflecting the physio-logic role of ERR␣, a number of ERR␣ target genes have been identified (15), and transcriptional function was shown to depend on chromatin environment of the promoters. Although no endogenous ligand has yet been found, synthetic ERR␣ ligands appear to modulate ERR␣ transcriptional activity as inverse antagonists (16,17). Although these findings suggest that ERR␣ is a potential interactant for co-activators and corepressors of transcription, only a few co-activators have been shown to support ERR␣ function (18 -20).…”

Molecular determinants of species-specific agonist and antagonist activity of a substituted flavone towards the aryl hydrocarbon receptor

“…Ultimately, a better understanding of these events will depend on obtaining the crystal structure of liganded (with diverse ligands) and ligand-free AhR. Crystal structure analyses of other receptors and proteins has yielded insight into mechanisms of, for example, conformational changes due to ligand accomodation, and protein-protein interactions [25,26].…”

Trichoplax, the simplest known animal, contains an estrogen-related receptor but no estrogen receptor: Implications for estrogen receptor evolution

“…Both vertebrate ERRs and invertebrate ERs are constitutively active and do not bind estradiol. The crystal structures of human ERRs [11][12][13][14] and a 3D model of octopus ER [33] indicates that their ligand-binding domains are too small to accommodate estradiol.…”

“…An explanation for the absence of steroid binding by ERRs came from analysis of the crystal structures of human ERRα [11,12] and ERRγ [13], which showed that the ligand binding site is too small to accommodate a steroid [11][12][13][14]. Unlike the ER, the ERR does not require a ligand to become transcriptionally active.…”