scholarly journals Delineation of the molecular determinants of the unique allosteric binding site of the orphan nuclear receptor RORγt

2020 ◽  
Vol 295 (27) ◽  
pp. 9183-9191
Author(s):  
Iris A. Leijten-van de Gevel ◽  
Luc Brunsveld
Keyword(s):  
Drug Discovery ◽  
Ligand Binding ◽  
Autoimmune Diseases ◽  
Retinoic Acid Receptor ◽  
Binding Pocket ◽  
Orphan Receptor ◽  
Interleukin 17 ◽  
Orphan Nuclear Receptor ◽  
T Helper 17 ◽  
Helix 12

Nuclear receptors (NRs) are high-interest targets in drug discovery because of their involvement in numerous biological processes and diseases. Classically, NRs are targeted via their hydrophobic, orthosteric pocket. Although successful, this approach comes with challenges, including off-target effects due to lack of selectivity. Allosteric modulation of NR activity constitutes a promising pharmacological strategy. The retinoic acid receptor-related orphan receptor-γt (RORγt) is a constitutively active NR that positively regulates the expression of interleukin-17 in T helper 17 cells. Inhibiting this process is an emerging strategy for managing autoimmune diseases. Recently, an allosteric binding pocket in the C-terminal region of the ligand-binding domain (LBD) of RORγt was discovered that is amenable to small-molecule drug discovery. Compounds binding this pocket induce a reorientation of helix 12, thereby preventing coactivator recruitment. Therefore, inverse agonists binding this site with high affinity are actively being pursued. To elucidate the pocket formation mechanism, verify the uniqueness of this pocket, and substantiate the relevance of targeting this site, here we identified the key characteristics of the RORγt allosteric region. We evaluated the effects of substitutions in the LBD on coactivator, orthosteric, and allosteric ligand binding. We found that two molecular elements unique to RORγt, the length of helix 11′ and a Gln-487 residue, are crucial for the formation of the allosteric pocket. The unique combination of elements present in RORγt suggests a high potential for subtype-selective targeting of this NR to more effectively treat patients with autoimmune diseases.

scholarly journals The nuclear receptor REV-ERBα modulates Th17 cell-mediated autoimmune disease

2019 ◽  
Vol 116 (37) ◽  
pp. 18528-18536 ◽  
Author(s):  
Christina Chang ◽  
Chin-San Loo ◽  
Xuan Zhao ◽  
Laura A. Solt ◽  
Yuqiong Liang ◽  
...  
Keyword(s):  
Autoimmune Diseases ◽  
Nuclear Receptor ◽  
Th17 Cells ◽  
Inflammatory Responses ◽  
Retinoic Acid Receptor ◽  
Nuclear Hormone Receptor ◽  
Interleukin 17 ◽  
Orphan Nuclear Receptor ◽  
T Helper 17 ◽  
Autoimmune Encephalomyelitis

T helper 17 (Th17) cells produce interleukin-17 (IL-17) cytokines and drive inflammatory responses in autoimmune diseases such as multiple sclerosis. The differentiation of Th17 cells is dependent on the retinoic acid receptor-related orphan nuclear receptor RORγt. Here, we identify REV-ERBα (encoded byNr1d1), a member of the nuclear hormone receptor family, as a transcriptional repressor that antagonizes RORγt function in Th17 cells. REV-ERBα binds to ROR response elements (RORE) in Th17 cells and inhibits the expression of RORγt-dependent genes includingIl17aandIl17f. Furthermore, elevated REV-ERBα expression or treatment with a synthetic REV-ERB agonist significantly delays the onset and impedes the progression of experimental autoimmune encephalomyelitis (EAE). These results suggest that modulating REV-ERBα activity may be used to manipulate Th17 cells in autoimmune diseases.

scholarly journals Unraveling the physiological roles of retinoic acid receptor-related orphan receptor α

2021 ◽  
Author(s):  
Ji Min Lee ◽  
Hyunkyung Kim ◽  
Sung Hee Baek
Keyword(s):  
Retinoic Acid ◽  
Molecular Mechanisms ◽  
Cancer Metabolism ◽  
Metabolic Diseases ◽  
Retinoic Acid Receptor ◽  
Critical Role ◽  
Orphan Receptor ◽  
Orphan Nuclear Receptor ◽  
Functional Link ◽  
Acid Receptor

AbstractRetinoic acid receptor-related orphan receptor-α (RORα) is a member of the orphan nuclear receptor family and functions as a transcriptional activator in response to circadian changes. Circadian rhythms are complex cellular mechanisms regulating diverse metabolic, inflammatory, and tumorigenic gene expression pathways that govern cyclic cellular physiology. Disruption of circadian regulators, including RORα, plays a critical role in tumorigenesis and facilitates the development of inflammatory hallmarks. Although RORα contributes to overall fitness among anticancer, anti-inflammatory, lipid homeostasis, and circadian clock mechanisms, the molecular mechanisms underlying the mode of transcriptional regulation by RORα remain unclear. Nonetheless, RORα has important implications for pharmacological prevention of cancer, inflammation, and metabolic diseases, and understanding context-dependent RORα regulation will provide an innovative approach for unraveling the functional link between cancer metabolism and rhythm changes.

scholarly journals Unique functional properties of a member of the Fushi Tarazu-Factor 1 family from Schistosoma mansoni

2004 ◽  
Vol 382 (1) ◽  
pp. 337-351 ◽  
Author(s):  
Benjamin BERTIN ◽  
Souphatta SASORITH ◽  
Stéphanie CABY ◽  
Frédérik OGER ◽  
Jocelyne CORNETTE ◽  
...  
Keyword(s):  
Amino Acids ◽  
Ligand Binding ◽  
Schistosoma Mansoni ◽  
Transcriptional Activity ◽  
Binding Pocket ◽  
Activation Function ◽  
Orphan Receptor ◽  
Fushi Tarazu ◽  
Dependent Activity ◽  
Arginine Residues

SmFtz-F1 (Schistosoma mansoni Fushi Tarazu-Factor 1) belongs to the Ftz-F1 subfamily of nuclear receptors, but displays marked structural differences compared with its mammalian homologues SF-1 (steroidogenic factor-1) or liver receptor homologue-1. These include a long F domain (104 amino acids), an unusually large hinge region (133 amino acids) and a poorly conserved E-domain. Here, using Gal4 constructs and a mammalian two-hybrid assay, we have characterized the roles of these specific regions both in the transcriptional activity of the receptor and in its interactions with cofactors. Our results have shown that, although the AF-2 (activation function-2) region is the major activation function of the receptor, both the F and D domains are essential for AF-2-dependent activity. Modelling of SmFtz-F1 LBD (ligand-binding domain) and structure-guided mutagenesis allowed us to show the important role of helix H1 in maintaining the structural conformation of the LBD, and suggested that its autonomous transactivation activity, also observed with SF-1, is fortuitous. This strategy also allowed us to study an eventual ligand-dependence for this orphan receptor, the predicted three-dimensional models suggesting that the SmFtz-F1 LBD contains a large and well-defined ligand-binding pocket sealed by two arginine residues orientated towards the interior of the cavity. Mutation of these two residues provoked a loss of transcriptional activity of the receptor, and strongly reduced its interaction with SRC1 (steroid receptor cofactor-1), suggesting a ligand-dependent activity for SmFtz-F1. Taken together, our results argue for original and specific functional activities for this platyhelminth nuclear receptor.

scholarly journals Fenofibrate Inhibited the Differentiation of T Helper 17 CellsIn Vitro

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Zhou Zhou ◽  
Weiliang Sun ◽  
Ying Liang ◽  
Yanxiang Gao ◽  
Wei Kong ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Autoimmune Diseases ◽  
Th17 Cells ◽  
Transforming Growth Factor ◽  
Inflammatory Diseases ◽  
Lipid Lowering ◽  
Interleukin 17 ◽  
T Helper ◽  
T Helper 17 ◽  
Th17 Differentiation

Uncontrolled activity of T cells mediates autoimmune and inflammatory diseases such as multiple sclerosis, inflammatory bowel diseases, rheumatoid arthritis, type 1 diabetes, and atherosclerosis. Recent findings suggest that enhanced activity of interleukin-17 (IL-17) producing T helper 17 cells (Th17 cells) plays an important role in autoimmune diseases and inflammatory diseases. Previous papers have revealed that a lipid-lowering synthetic ligand of peroxisome proliferator-activated receptorα(PPARα), fenofibrate, alleviates both atherosclerosis and a few nonlipid-associated autoimmune diseases such as autoimmune colitis and multiple sclerosis. However, the link between fenofibrate and Th17 cells is lacking. In the present study, we hypothesized that fenofibrate inhibited the differentiation of Th17 cells. Our results showed that fenofibrate inhibited transforming growth factor-β(TGF-β) and IL-6-induced differentiation of Th17 cellsin vitro. However, other PPARαligands such as WY14643, GW7647 and bezafibrate did not show any effect on Th17 differentiation, indicating that this effect of fenofibrate might be PPARαindependent. Furthermore, our data showed that fenofibrate reduced IL-21 production and STAT3 activation, a critical signal in the Th17 differentiation. Thus, by ameliorating the differentiation of Th17 cells, fenofibrate might be beneficial for autoimmunity and inflammatory diseases.

IL-17/IL-17 receptor system in autoimmune disease: mechanisms and therapeutic potential

2012 ◽  
Vol 122 (11) ◽  
pp. 487-511 ◽  
Author(s):  
Shu Zhu ◽  
Youcun Qian
Keyword(s):  
Autoimmune Diseases ◽  
Therapeutic Potential ◽  
Fungal Infections ◽  
Current Knowledge ◽  
Critical Role ◽  
Cell Subset ◽  
Interleukin 17 ◽  
T Helper 17 ◽  
Receptor System ◽  
Inflammatory Autoimmune Diseases

IL-17 (interleukin-17), a hallmark cytokine of Th17 (T-helper 17) cells, plays critical roles in host defence against bacterial and fungal infections, as well as in the pathogenesis of autoimmune diseases. The present review focuses on current knowledge of the regulation, functional mechanisms and targeting strategies of IL-17 in the context of inflammatory autoimmune diseases. Evidence shows that IL-17 is highly up-regulated at sites of inflammatory tissues of autoimmune diseases and amplifies the inflammation through synergy with other cytokines, such as TNF (tumour necrosis factor) α. Although IL-17 was originally thought to be produced mainly by Th17 cells, a newly defined T-cell subset with a specific differentiation programme and tight regulation, several other cell types (especially innate immune cells) are also found as important sources for IL-17 production. Although IL-17 activates common downstream signalling, including NF-κB (nuclear factor κB), MAPKs (mitogen-activated protein kinases), C/EBPs (CCAAT/enhancer-binding proteins) and mRNA stability, the immediate receptor signalling has been shown to be quite unique and tightly regulated. Mouse genetic studies have demonstrated a critical role for IL-17 in the pathogenesis of variety of inflammatory autoimmune diseases, such as RA (rheumatoid arthritis) and MS (multiple sclerosis). Importantly, promising results have been shown in initial clinical trials of monoclonal antibodies against IL-17 or its receptor (IL-17R) to block IL-17-mediated function in treating autoimmune patients with psoriasis, RA and MS. Therefore targeting IL-17/IL-17R, IL-17-producing pathways or IL-17-mediated signalling pathways can be considered for future therapy in autoimmune diseases.

scholarly journals RORγ Structural Plasticity and Druggability

2020 ◽  
Author(s):  
Mian Huang ◽  
Shelby Bolin ◽  
Hannah Miller ◽  
Ho Leung Ng
Keyword(s):  
Crystal Structures ◽  
Structural Information ◽  
Dynamic Properties ◽  
Retinoic Acid Receptor ◽  
Structural Plasticity ◽  
Orphan Receptor ◽  
T Helper 17 ◽  
Atomic Interactions ◽  
Allosteric Binding Sites

Retinoic acid receptor-related orphan receptor γ (RORγ) is a transcription factor regulating the expression of the pro-inflammatory cytokine IL-17 in human T helper 17 (Th17) cells. Activating RORγ can induce multiple IL-17-mediated autoimmune diseases but may also be useful for anticancer therapy. Its deep immunological functions make RORɣ an attractive drug target. Over 70 crystal structures have been published describing atomic interactions between RORɣ and agonists and inverse agonists. In this review, we focus on the role of dynamic properties and plasticity of the RORɣ orthosteric and allosteric binding sites by examining structural information from crystal structures and simulated models. We discuss the possible influences of allosteric ligands on the orthosteric binding site. We find that high structural plasticity favors the druggability of RORɣ, especially for allosteric ligands.

scholarly journals Correction to ‘Evolutionary diversification of retinoic acid receptor ligand-binding pocket structure by molecular tinkering'

2016 ◽  
Vol 3 (12) ◽  
pp. 160895
Author(s):  
Julianan Gutierrez-Mazariegos ◽  
Eswar Kumar Nadendla ◽  
Romain A. Studer ◽  
Susana Alvarez ◽  
Angel R. de Lera ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Ligand Binding ◽  
Retinoic Acid Receptor ◽  
Binding Pocket ◽  
Receptor Ligand ◽  
Ligand Binding Pocket ◽  
Acid Receptor ◽  
Evolutionary Diversification

Discovery and Optimization of a Series of Sulfonamide Inverse Agonists for the Retinoic Acid Receptor-Related Orphan Receptor-α

2019 ◽  
Vol 15 (6) ◽  
pp. 676-684
Author(s):  
Christelle Doebelin ◽  
Yuanjun He ◽  
Sean Campbell ◽  
Philippe Nuhant ◽  
Naresh Kumar ◽  
...  
Keyword(s):  
Retinoic Acid Receptor ◽  
Research Effort ◽  
Pharmacokinetic Profile ◽  
Orphan Receptor ◽  
Orphan Nuclear Receptor ◽  
Inverse Agonists ◽  
Close Family Member ◽  
Per Oral

Background: Despite a massive industry endeavor to develop RORγ-modulators for autoimmune disorders, there has been no indication of efforts to target the close family member RORα for similar indications. This may be due to the misconception that RORα is redundant to RORγ, or the inherent difficulty in cultivating tractable starting points for RORα. RORα-selective modulators would be useful tools to interrogate the biology of this understudied orphan nuclear receptor. Objectives: he goal of this research effort was to identify and optimize synthetic ligands for RORα starting from the known LXR agonist T0901317. Methods: Fourty-five analogs of the sulfonamide lead (1) were synthesized and evaluated for their ability to suppress the transcriptional activity of RORα, RORγ, and LXRα in cell-based assays. Analogs were characterized by 1H-NMR, 13C-NMR, and LC-MS analysis. The pharmacokinetic profile of the most selective RORα inverse agonist was evaluated in rats with intraperitoneal (i.p.) and per oral (p.o.)dosing. Results: Structure-activity relationship studies led to potent dual RORα/RORγ inverse agonists as well as RORα-selective inverse agonists (20, 28). LXR activity could be reduced by removing the sulfonamide nitrogen substituent. Attempts to improve the potency of these selective leads by varying substitution patterns throughout the molecule proved challenging. Conclusion: The synthetic RORα-selective inverse agonists identified (20, 28) can be utilized as chemical tools to probe the function of RORα in vitro and in vivo.

Sign in / Sign up

Export Citation Format

Share Document