Molecular determinants of the recognition of ulipristal acetate by oxo-steroid receptors

Petit-Topin, Isabelle; Fay, Michèle; Resche-Rigon, Matthieu; Ulmann, André; Gainer, Erin; Rafestin‐Oblin, Marie‐Edith; Fagart, Jérôme

doi:10.1016/j.jsbmb.2014.08.008

Cited by 40 publications

(27 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The corepressor peptide binds to the AF-2 surface through interactions with helix 3 and helix 4/5, but unlike the active conformation the peptide does not contact helix 12. As observed in other crystal structures of corepressor-peptide-bound NR LBDs [3][4][5][6][7][8][9][11][12][13][14] , there is an extension of the corepressor peptide by one helical turn relative to the coactivator peptide that would physically clash with helix 12 in the active conformation. Instead, helix 12 occupies the orthosteric ligand-binding pocket overlapping with the active conformation rosiglitazone orthosteric binding mode (Fig.…”

Section: Crystal Structures Of the Repressive Conformation Of Pparγsupporting

confidence: 60%

“…Agonist binding to the NR orthosteric ligand-binding pocket stabilizes the C-terminal structural element in the LBD, helix 12, in an active conformation that facilitates binding of LXXLL-containing motifs present in transcriptional coactivator proteins. In contrast, structural studies available for only a few NRs have not revealed a unified mechanism for repression of NR transcription [3][4][5][6][7][8][9][10][11][12][13][14] , suggesting that corepressor-dependent transcriptional repression of NRs occurs through structurally diverse mechanisms. Furthermore, the conformational ensemble of helix 12 in apo-NR LBDs, which is hypothesized to exchange between a transcriptionally active conformation and a repressive conformation, remains poorly defined.…”

mentioning

confidence: 96%

See 1 more Smart Citation

A molecular switch regulating transcriptional repression and activation of PPARγ

et al. 2020

View full text Add to dashboard Cite

Nuclear receptor (NR) transcription factors use a conserved activation function-2 (AF-2) helix 12 mechanism for agonist-induced coactivator interaction and NR transcriptional activation. In contrast, ligand-induced corepressor-dependent NR repression appears to occur through structurally diverse mechanisms. We report two crystal structures of peroxisome proliferator-activated receptor gamma (PPARγ) in an inverse agonist/corepressor-bound transcriptionally repressive conformation. Helix 12 is displaced from the solvent-exposed active conformation and occupies the orthosteric ligand-binding pocket enabled by a conformational change that doubles the pocket volume. Paramagnetic relaxation enhancement (PRE) NMR and chemical crosslinking mass spectrometry confirm the repressive helix 12 conformation. PRE NMR also defines the mechanism of action of the corepressor-selective inverse agonist T0070907, and reveals that apo-helix 12 exchanges between transcriptionally active and repressive conformations-supporting a fundamental hypothesis in the NR field that helix 12 exchanges between transcriptionally active and repressive conformations.

show abstract

Section: Crystal Structures Of the Repressive Conformation Of Pparγsupporting

confidence: 60%

mentioning

confidence: 96%

A molecular switch regulating transcriptional repression and activation of PPARγ

et al. 2020

View full text Add to dashboard Cite

show abstract

“…1). Lysates were also incubated with [ 3 H]cortisol plus 500-fold excess of RU486, which was unable to bind MRs (30). As expected, RU486 displaced [ 3 H]cortisol binding from GRs, but not from MRs (Supplemental Fig.…”

Section: Validation Of Cellular and Molecular Toolsmentioning

confidence: 52%

Corticosteroid receptors adopt distinct cyclical transcriptional signatures

et al. 2018

View full text Add to dashboard Cite

Mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) are two closely related hormone-activated transcription factors that regulate major pathophysiologic functions. High homology between these receptors accounts for the crossbinding of their corresponding ligands, MR being activated by both aldosterone and cortisol and GR essentially activated by cortisol. Their coexpression and ability to bind similar DNA motifs highlight the need to investigate their respective contributions to overall corticosteroid signaling. Here, we decipher the transcriptional regulatory mechanisms that underlie selective effects of MRs and GRs on shared genomic targets in a human renal cellular model. Kinetic, serial, and sequential chromatin immunoprecipitation approaches were performed on the period circadian protein 1 ( PER1) target gene, providing evidence that both receptors dynamically and cyclically interact at the same target promoter in a specific and distinct transcriptional signature. During this process, both receptors regulate PER1 gene by binding as homo- or heterodimers to the same promoter region. Our results suggest a novel level of MR-GR target gene regulation, which should be considered for a better and integrated understanding of corticosteroid-related pathophysiology.-Le Billan, F., Amazit, L., Bleakley, K., Xue, Q.-Y., Pussard, E., Lhadj, C., Kolkhof, P., Viengchareun, S., Fagart, J., Lombès, M. Corticosteroid receptors adopt distinct cyclical transcriptional signatures.

show abstract

“…Taking the crystal antagonistic structure models (PDB ID 2OVH, Fig 1B) as an example, helix 12 is displaced from the surface of the LBD core and is antiparallel to helix 11, while the co-peptides (12 residues), which are a the common sequences in NCoR peptide (25 residues), occupy the hydrophobic groove formed by helix 3 and helix 4. The antagonists of PR LBD bind to the same binding pocket as progesterone does, whereas the unusually large 11β-substituted group of some antagonists prevent helix 12 from contacting with helix 3 [19,20]. In more detail, the antagonist 11β-substituted group adopts the conformational space where Met908 and Met909 in helix 12 used to take, therefore it was believed the relatively large size of 11β-substituted group contributes to the antagonistic conformation [19].…”

Section: Introductionmentioning

confidence: 99%

Exploring Flexibility of Progesterone Receptor Ligand Binding Domain Using Molecular Dynamics

Zheng

Lin

2016

PLoS ONE

View full text Add to dashboard Cite

Progesterone receptor (PR), a member of nuclear receptor (NR) superfamily, plays a vital role for female reproductive tissue development, differentiation and maintenance. PR ligand, such as progesterone, induces conformation changes in PR ligand binding domain (LBD), thus mediates subsequent gene regulation cascades. PR LBD may adopt different conformations upon an agonist or an antagonist binding. These different conformations would trigger distinct transcription events. Therefore, the dynamics of PR LBD would be of general interest to biologists for a deep understanding of its structure-function relationship. However, no apo-form (non-ligand bound) of PR LBD model has been proposed either by experiments or computational methods so far. In this study, we explored the structural dynamics of PR LBD using molecular dynamics simulations and advanced sampling tools in both ligand-bound and the apo-forms. Resolved by the simulation study, helix 11, helix 12 and loop 895–908 (the loop between these two helices) are quite flexible in antagonistic conformation. Several residues, such as Arg899 and Glu723, could form salt-bridging interaction between helix 11 and helix 3, and are important for the PR LBD dynamics. And we also propose that helix 12 in apo-form PR LBD, not like other NR LBDs, such as human estrogen receptor α (ERα) LBD, may not adopt a totally extended conformation. With the aid of umbrella sampling and metadynamics simulations, several stable conformations of apo-form PR LBD have been sampled, which may work as critical structural models for further large scale virtual screening study to discover novel PR ligands for therapeutic application.

show abstract

Molecular determinants of the recognition of ulipristal acetate by oxo-steroid receptors

Cited by 40 publications

References 61 publications

A molecular switch regulating transcriptional repression and activation of PPARγ

A molecular switch regulating transcriptional repression and activation of PPARγ

Corticosteroid receptors adopt distinct cyclical transcriptional signatures

Exploring Flexibility of Progesterone Receptor Ligand Binding Domain Using Molecular Dynamics

Contact Info

Product

Resources

About