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 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 100 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 RORγ Structural Plasticity and Druggability

2020 ◽  
Vol 21 (15) ◽  
pp. 5329
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 100 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.

Investigating the dynamic nature of the ABC transporters: ABCB1 and MsbA as examples for the potential synergies of MD theory and EPR applications

2015 ◽  
Vol 43 (5) ◽  
pp. 1023-1032 ◽  
Author(s):  
Thomas Stockner ◽  
Anna Mullen ◽  
Fraser MacMillan
Keyword(s):  
Crystal Structures ◽  
Conformational Changes ◽  
Abc Transporters ◽  
Epr Spectroscopy ◽  
Structural Information ◽  
Dynamic Properties ◽  
Molecular System ◽  
Synergistic Effects ◽  
Md Simulations ◽  
Substrate Spectrum

ABC transporters are primary active transporters found in all kingdoms of life. Human multidrug resistance transporter ABCB1, or P-glycoprotein, has an extremely broad substrate spectrum and confers resistance against chemotherapy drug treatment in cancer cells. The bacterial ABC transporter MsbA is a lipid A flippase and a homolog to the human ABCB1 transporter, with which it partially shares its substrate spectrum. Crystal structures of MsbA and ABCB1 have been solved in multiple conformations, providing a glimpse into the possible conformational changes the transporter could be going through during the transport cycle. Crystal structures are inherently static, while a dynamic picture of the transporter in motion is needed for a complete understanding of transporter function. Molecular dynamics (MD) simulations and electron paramagnetic resonance (EPR) spectroscopy can provide structural information on ABC transporters, but the strength of these two methods lies in the potential to characterise the dynamic regime of these transporters. Information from the two methods is quite complementary. MD simulations provide an all atom dynamic picture of the time evolution of the molecular system, though with a narrow time window. EPR spectroscopy can probe structural, environmental and dynamic properties of the transporter in several time regimes, but only through the attachment sites of an exogenous spin label. In this review the synergistic effects that can be achieved by combining the two methods are highlighted, and a brief methodological background is also presented.

scholarly journals Deletion of the nuclear receptor RORα in macrophages does not modify the development of obesity, insulin resistance and NASH

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Laurent L’homme ◽  
Benan Pelin Sermikli ◽  
Olivier Molendi-Coste ◽  
Sébastien Fleury ◽  
Sandrine Quemener ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Nuclear Receptor ◽  
High Fat Diet ◽  
Cell Function ◽  
Retinoic Acid Receptor ◽  
Orphan Receptor ◽  
Nuclear Receptor Family ◽  
Receptor Family ◽  
Diet Model

AbstractRetinoic acid receptor-related orphan receptor-alpha (RORα) is a transcription factor from the nuclear receptor family expressed by immune cells and involved in the development of obesity, insulin resistance (IR) and non-alcoholic steatohepatitis (NASH). It was recently reported that mice deficient for RORα in macrophages develop more severe NASH upon high fat diet (HFD) feeding due to altered Kupffer cell function. To better understand the role of RORα in obesity and IR, we independently generated a macrophage RORα-deficient mouse line. We report that RORα deletion in macrophages does not impact on HFD-induced obesity and IR. Surprisingly, we did not confirm an effect on NASH development upon HFD feeding nor in the more severe and obesity-independent choline-deficient, L-amino acid-defined diet model. Our results therefore show that RORα deletion in macrophages does not alter the development of obesity and IR and question its role in NASH.

RORα contributes to the maintenance of genome ploidy in the liver of mice with diet-induced nonalcoholic steatohepatitis

2021 ◽  
Author(s):  
Ju-Yeon Kim ◽  
In Sook Yang ◽  
Hyeon-Ji Kim ◽  
Jae-Yeun Yoon ◽  
Yong-Hyun Han ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Retinoic Acid Receptor ◽  
Orphan Receptor ◽  
Rna Seq ◽  
Ontology Term ◽  
Nonalcoholic Fatty Liver ◽  
Search Tool ◽  
Dna Endoreplication ◽  
Genome Ploidy

Hepatic polyploidization is closely linked to the progression of nonalcoholic fatty liver disease (NAFLD); however, the underlying molecular mechanism is not clearly understood. In this study, we demonstrated the role of RORα in the maintenance of genomic integrity, particularly in the pathogenesis of NAFLD, using the high-fat diet (HFD)-fed liver-specific RORα knockout (RORα-LKO) mouse model. First, we observed that the loss of hepatic retinoic acid receptor-related orphan receptor α (RORα) accelerated hepatocyte nuclear polyploidization after HFD feeding. In 70% partial hepatectomy experiments, enrichment of hepatocyte polyploidy was more obvious in the RORα-LKO animals, which was accompanied by early progression to the S phase and blockade of the G2/M transition, suggesting a potential role of RORα in suppressing hepatocyte polyploidization in the regenerating liver. An analysis of a publicly available RNA-seq and chromatin immunoprecipitation-seq dataset, together with the Search Tool of the Retrieval of Interacting Genes/Proteins database resource, revealed that DNA endoreplication was the top enriched biological process gene ontology term. Furthermore, we found that E2f7 and E2f8, which encode key transcription factors for DNA endoreplication, were the downstream targets of RORα-induced transcriptional repression. Finally, we showed that the administration of JC1-40, an RORα activator (5 mg/kg body weight), significantly reduced hepatic nuclear polyploidization in the HFD-fed mice. Together, our observations suggest that the RORα-induced suppression of hepatic polyploidization may provide new insights into the pathological polyploidy of NAFLD and may contribute to the development of therapeutic strategies for the treatment of NAFLD.

scholarly journals Serine 182 on RORγt regulates T helper 17 and regulatory T cell functions to resolve inflammation

2021 ◽  
Author(s):  
Shengyun Ma ◽  
Shefali Patel ◽  
Nicholas Chen ◽  
Parth R Patel ◽  
Benjamin S Cho ◽  
...  
Keyword(s):  
T Cell ◽  
Treg Cells ◽  
Orphan Receptor ◽  
T Helper 17 ◽  
Autoimmune Encephalomyelitis ◽  
Tissue Inflammation ◽  
Cell Functions ◽  
Autoimmune Conditions ◽  
Delayed Recovery

Unresolved inflammation causes tissue damage and contributes to autoimmune conditions. However, the molecules and mechanisms controlling T cell mediated inflammation remain to be fully elucidated. Here, we report an unexpected role of the RAR-Related Orphan Receptor-gamma protein (RORγt) in resolving tissue inflammation. Single-cell RNA-seq (scRNA-seq) revealed that an evolutionarily conserved serine 182 residue on ROR&γt (RORγtS182) is critical for restricting IL-1β-mediated Th17 activities and promoting anti-inflammatory cytokine IL-10 production in RORγt+ Treg cells in inflamed tissues. Phospho-null RORγtS182A knock-in mice experienced delayed recovery and succumbed to exacerbated diseases after dextran sulfate sodium (DSS) induced colitis and experimental autoimmune encephalomyelitis (EAE) challenge. Together, these results highlight the essential role of ROR&γtS182 in resolving T cell mediated tissue inflammation, providing a potential therapeutic target to combat autoimmune diseases.

scholarly journals In vivo equilibrium of proinflammatory IL-17+ and regulatory IL-10+ Foxp3+ RORγt+ T cells

2008 ◽  
Vol 205 (6) ◽  
pp. 1381-1393 ◽  
Author(s):  
Matthias Lochner ◽  
Lucie Peduto ◽  
Marie Cherrier ◽  
Shinichiro Sawa ◽  
Francina Langa ◽  
...  
Keyword(s):  
T Cells ◽  
Retinoic Acid Receptor ◽  
Cell Receptor ◽  
Nuclear Hormone Receptor ◽  
Orphan Receptor ◽  
T Helper ◽  
T Helper 17 ◽  
Infection And Inflammation ◽  
And Function

The nuclear hormone receptor retinoic acid receptor–related orphan receptor γt (RORγt) is required for the generation of T helper 17 cells expressing the proinflammatory cytokine interleukin (IL)-17. In vivo, however, less than half of RORγt+ T cells express IL-17. We report here that RORγt+ Tαβ cells include Foxp3+ cells that coexist with IL-17–producing RORγt+ Tαβ cells in all tissues examined. The Foxp3+ RORγt+ Tαβ express IL-10 and CCL20, and function as regulatory T cells. Furthermore, the ratio of Foxp3+ to IL-17–producing RORγt+ Tαβ cells remains remarkably constant in mice enduring infection and inflammation. This equilibrium is tuned in favor of IL-10 production by Foxp3 and CCL20, and in favor of IL-17 production by IL-6 and IL-23. In the lung and skin, the largest population of RORγt+ T cells express the γδ T cell receptor and produce the highest levels of IL-17 independently of IL-6. Thus, potentially antagonistic proinflammatory IL-17–producing and regulatory Foxp3+ RORγt+ T cells coexist and are tightly controlled, suggesting that a perturbed equilibrium in RORγt+ T cells might lead to decreased immunoreactivity or, in contrast, to pathological inflammation.

scholarly journals The role of Th17/Treg-mediated immunoregulation in abortion mice

2018 ◽  
Vol 16 ◽  
pp. 205873921876035 ◽  
Author(s):  
Ning Li ◽  
Qinglan Qu ◽  
Qian Yan
Keyword(s):  
Spontaneous Abortion ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Normal Pregnancy ◽  
Treg Cells ◽  
Vital Role ◽  
Orphan Receptor ◽  
T Helper ◽  
T Helper 17

In the study, we investigated the immune factors related to T helper 17 (Th17) cells and T regulatory (Treg) cells in spontaneous abortion mice. The expression of Th17 was analyzed by interleukin (IL)-6, IL-17A secretion, RAR-related orphan receptor γt (RORγt) expression, and proportion of CD4+IL-17+ cells. The levels of IL-10, transforming growth factor β (TGF-β), Foxp3, and CD4+Foxp3+ cells were presented the Treg expression. Higher embryo absorption rate was found in spontaneous abortion group than that in normal pregnancy group ( P < 0.01). Compared with the normal pregnancy mice, spontaneous abortion mice showed higher levels of IL-6 and IL-17A and lower levels of IL-10 and TGF-β in serum and in decidua ( P < 0.05). Furthermore, the expressions of Foxp3 and CD4+Foxp3+ cells were significantly decreased in spontaneous abortion mice than those in normal pregnancy mice ( P < 0.05). However, the levels of RORγt and CD4+IL-17+ cells remarkably increased in spontaneous abortion mice ( P < 0.05). The results reveal that Th17/Treg cells may play a vital role in immunoregulation during pregnancy.

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.

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