Allosteric pathways in nuclear receptors — Potential targets for drug design

Fernandez, Elias J.

doi:10.1016/j.pharmthera.2017.10.014

Cited by 24 publications

(16 citation statements)

References 145 publications

(196 reference statements)

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“…2A) (Nadal et al 2017). In multidomain AR, both intra-and interdomain allostery may occur simultaneously (Fernandez et al 2017, Fernandez 2018. The first may take place within the NTD, DBD or LBD moieties, while interdomain signal transduction appears to be essential in coordinating AR functions (e.g., through the well-studied N-C contacts, but also upon as of yet uncharacterized DBD-LBD and LBD-DNA interactions).…”

Section: Figurementioning

confidence: 99%

Non-canonical dimerization of the androgen receptor and other nuclear receptors: implications for human disease

Jiménez-Panizo

Pérez

Rojas

et al. 2019

Endocrine-Related Cancer

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Nuclear receptors are transcription factors that play critical roles in development, homeostasis and metabolism in all multicellular organisms. An important family of nuclear receptors comprises those members that respond to steroid hormones, and which is subdivided in turn into estrogen receptor (ER) isoforms α and β (NR3A1 and A2, respectively), and a second subfamily of so-called oxosteroid receptors. The latter includes the androgen receptor (AR/NR3C4), the glucocorticoid receptor (GR/NR3C1), the mineralocorticoid receptor (MR/NR3C2) and the progesterone receptor (PR/NR3C3). Here we review recent advances in our understanding of the structure-and-function relationship of steroid nuclear receptors and discuss their implications for the etiology of human diseases. We focus in particular on the role played by AR dysregulation in both prostate cancer (PCa) and androgen insensitivity syndromes (AIS), but also discuss conditions linked to mutations of the GR gene as well as those in a non-steroidal receptor, the thyroid hormone receptor (TR). Finally, we explore how these recent results might be exploited for the development of novel and selective therapeutic strategies.

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Section: Figurementioning

confidence: 99%

Non-canonical dimerization of the androgen receptor and other nuclear receptors: implications for human disease

Jiménez-Panizo

Pérez

Rojas

et al. 2019

Endocrine-Related Cancer

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“…ligand binding, mutations) induce effects at a distal site. Mechanisms of allostery in NRs have been heavily reviewed [41][42][43][44][45][46][47] (ii) DNA-coregulator allosteric coupling. NR DBD binding to DNA response elements propagates conformational changes across protein domains, extending to the AF-2 surface and allosterically regulating coregulator association [46,54] ( Figure 3C).…”

Section: Interdomain Allostery In Nrsmentioning

confidence: 99%

“…Similarly, the presence of thyroid receptor (TR) response elements alters TR binding affinity for various coregulator peptides [58]. Evidence also exists indicating that response element sequence can modulate NR coregulator preferences [41].…”

Section: Interdomain Allostery In Nrsmentioning

confidence: 99%

Ligand-Induced Allosteric Effects Governing SR Signaling

Okafor¹,

Colucci²,

Ortlund³

2019

Nuclear Receptor Research

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Steroid receptors (SRs) are a class of ligand-regulated transcription factors that regulate gene expression in response to the binding of steroid hormones. Ligand binding drives conformational changes within the SR ligand binding domain that alters the receptors' affinity for coregulator proteins that in turn modulate chromatin state and either promote or block the recruitment of transcriptional machinery to a gene. Structural characterizations of SRs have provided insight into how these conformational rearrangements modulate receptor function, including signaling between the ligand binding pocket and the site of coregulator binding. Here, we review some of the proposed structural mechanisms put forward to explain the ability of ligands to modulate SR function. We also provide a discussion on computational methods that have contributed to the elucidation of SR allosteric regulation. Finally, we consider broader discussions of allostery within the SR family, such as receptor-induced reverse allostery and allosteric binding sites located outside of the canonical ligand interaction site.

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“…Dimerization renders the control of NR function intricate, because the signal across the heterodimer interface provides an exquisite degree of combinatorial control of transactivation (13). Within nuclear receptors, allostery is increasingly recognized as a common regulatory process initiated by DNA, ligands, and coregulators (14). Previous studies have defined an energetic coupled network of amino acids that mediates the allosteric regulation in RXR heterodimers using the statistic coupling analysis (SCA) method.…”

Section: Nuclear Receptor Farnesoid X Receptor (Fxr) Functions As Thementioning

confidence: 99%

Ligand binding and heterodimerization with retinoid X receptor α (RXRα) induce farnesoid X receptor (FXR) conformational changes affecting coactivator binding

Wang

Zou

et al. 2018

Journal of Biological Chemistry

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Edited by Dennis R. VoelkerNuclear receptor farnesoid X receptor (FXR) functions as the major bile acid sensor coordinating cholesterol metabolism, lipid homeostasis, and absorption of dietary fats and vitamins. Because of its central role in metabolism, FXR represents an important drug target to manage metabolic and other diseases, such as primary biliary cirrhosis and nonalcoholic steatohepatitis. FXR and nuclear receptor retinoid X receptor ␣ (RXR␣) form a heterodimer that controls the expression of numerous downstream genes. To date, the structural basis and functional consequences of the FXR/RXR heterodimer interaction have remained unclear. Herein, we present the crystal structures of the heterodimeric complex formed between the ligand-binding domains of human FXR and RXR␣. We show that both FXR and RXR bind to the transcriptional coregulator steroid receptor coactivator 1 with higher affinity when they are part of the heterodimer complex than when they are in their respective monomeric states. Furthermore, structural comparisons of the FXR/ RXR␣ heterodimers and the FXR monomers bound with different ligands indicated that both heterodimerization and ligand binding induce conformational changes in the C terminus of helix 11 in FXR that affect the stability of the coactivator binding surface and the coactivator binding in FXR. In summary, our findings shed light on the allosteric signal transduction in the FXR/RXR heterodimer, which may be utilized for future drug development targeting FXR.

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Allosteric pathways in nuclear receptors — Potential targets for drug design

Cited by 24 publications

References 145 publications

Non-canonical dimerization of the androgen receptor and other nuclear receptors: implications for human disease

Non-canonical dimerization of the androgen receptor and other nuclear receptors: implications for human disease

Ligand-Induced Allosteric Effects Governing SR Signaling

Ligand binding and heterodimerization with retinoid X receptor α (RXRα) induce farnesoid X receptor (FXR) conformational changes affecting coactivator binding

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