Modulation of nuclear receptor function: Targeting the protein-DNA interface.

Nuclear receptors (NRs) are a superfamily of ligand-dependent transcription factors that modulate several biological processes. Traditionally, modulation of NRs has been focused on the development of ligands that recognize and bind to the ligand binding domain (LBD), resulting in activation or repression of transcription through the recruitment of coregulators. However, for more severe diseases, such as breast and prostate cancer, the conventional treatment addressing LBD modulation is not always successful, due to tumor resistance. To overcome these challenges and aiming to modulate NR activity by inhibiting the NR-DNA interaction, new studies focus on the development of molecules targeting alternative sites and domains on NRs. Here, we discuss two different approaches for this alternative NR modulation: one targeting the NR DNA binding domain (DBD); and the other targeting the DNA sites recognized by NRs. Our aim is to present the challenges and perspectives for developing specific inhibitors for each purpose, alongside with already reported examples.

• Publication year

  2019

• Venue

  Molecular and Cellular Endocrinology

• Publication date

  2019-03-01

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1016/j.mce.2019.01.023PMID 30703486
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Multidomain architecture of estrogen receptor reveals interfacial cross-talk between its DNA-binding and ligand-binding domains

  2018cited by this paper
• A high-throughput fluorescence polarization assay for discovering inhibitors targeting the DNA-binding domain of signal transducer and activator of transcription 3 (STAT3)

  2018cited by this paper
• Selectively targeting the dimerization interface of human androgen receptor with small-molecules to treat castration-resistant prostate cancer.

  2018cited by this paper
• The first crystal structure of a DNA-free nuclear receptor DNA binding domain sheds light on DNA-driven allostery in the glucocorticoid receptor

  2018cited by this paper
• Structural basis of DNA duplex distortion induced by thiazole-containing hairpin polyamides

  2017cited by this paper
• The quaternary architecture of RARβ–RXRα heterodimer facilitates domain–domain signal transmission

  2017cited by this paper
• SelexGLM differentiates androgen and glucocorticoid receptor DNA-binding preference over an extended binding site

  2017cited by this paper
• A Pyrrole-Imidazole Polyamide Is Active against Enzalutamide-Resistant Prostate Cancer.

  2017cited by this paper
• Covalent inhibitors design and discovery.

  2017cited by this paper
• Therapeutic Interventions of Cancers Using Intrinsically Disordered Proteins as Drug Targets: c-Myc as Model System

  2017cited by this paper
• A DNA-binding Molecule Targeting the Adaptive Hypoxic Response in Multiple Myeloma Has Potent Antitumor Activity

  2016cited by this paper
• Historical overview of nuclear receptors.

  2016cited by this paper
• Sequences flanking the core-binding site modulate glucocorticoid receptor structure and activity

  2016cited by this paper
• A designed DNA binding motif that recognizes extended sites and spans two adjacent major grooves

  2016cited by this paper
• Visualizing the Architectures and Interactions of Nuclear Receptors.

  2016cited by this paper
• Covalent inhibitors in drug discovery: from accidental discoveries to avoided liabilities and designed therapies.

  2015cited by this paper
• Binding cavities and druggability of intrinsically disordered proteins

  2015cited by this paper
• Family reunion of nuclear hormone receptors: structures, diseases, and drug discovery

  2015cited by this paper
• Nuclear receptor full-length architectures: confronting myth and illusion with high resolution.

  2015cited by this paper
• Structure of a biologically active estrogen receptor-coactivator complex on DNA.

  2015cited by this paper
• Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer

  2015cited by this paper
• Signaling through retinoic acid receptors in cardiac development: Doing the right things at the right times.

  2015cited by this paper
• Relationship of Structure and Function of DNA-Binding Domain in Vitamin D Receptor

  2015cited by this paper
• An HRE-Binding Py-Im Polyamide Impairs Hypoxic Signaling in Tumors

  2015cited by this paper
• Minireview: Tipping the balance: ligand-independent activation of steroid receptors.

  2015cited by this paper
• Elevated expression of TANK-binding kinase 1 enhances tamoxifen resistance in breast cancer

  2014cited by this paper
• KVFinder: steered identification of protein cavities as a PyMOL plugin

  2014cited by this paper
• Ligand-independent and tissue-selective androgen receptor inhibition by pyrvinium.

  2014cited by this paper
• Structure of the retinoid X receptor alpha-liver X receptor beta (RXR alpha-LXR beta ) heterodimer on DNA.

  2014cited by this paper
• Structure of the retinoid X receptor α–liver X receptor β (RXRα–LXRβ) heterodimer on DNA

  2014cited by this paper
• Selectively Targeting the DNA-binding Domain of the Androgen Receptor as a Prospective Therapy for Prostate Cancer*

  2014cited by this paper
• Discovery of small-molecule inhibitors selectively targeting the DNA-binding domain of the human androgen receptor.

  2014cited by this paper
• Stilbene Induced Inhibition of Androgen Receptor Dimerization: Implications for AR and ARΔLBD-Signalling in Human Prostate Cancer Cells

  2014cited by this paper
• Understanding nuclear receptor form and function using structural biology.

  2013cited by this paper
• Antitumor activity of a pyrrole-imidazole polyamide

  2013cited by this paper
• Multi-Domain Integration in the Structure of the HNF4α Nuclear Receptor Complex

  2013cited by this paper
• DNA Binding Polyamides and the Importance of DNA Recognition in their use as Gene-Specific and Antiviral Agents.

  2013cited by this paper
• Binding site detection and druggability prediction of protein targets for structure-based drug design.

  2013cited by this paper
• Structure‐Based DNA‐Targeting Strategies with Small Molecule Ligands for Drug Discovery

  2013cited by this paper
• Beyond the Ligand‐Binding Pocket: Targeting Alternate Sites in Nuclear Receptors

  2013cited by this paper
• Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade.

  2013cited by this paper
• The Orphan Nuclear Receptor DAX-1 Functions as a Potent Corepressor of the Constitutive Androstane Receptor (NR1I3)

  2012cited by this paper
• General molecular biology and architecture of nuclear receptors.

  2012cited by this paper
• Small-molecule inhibitors of dimeric transcription factors: Antagonism of protein–protein and protein–DNA interactions

  2012cited by this paper
• Structural basis for nuclear hormone receptor DNA binding.

  2012cited by this paper
• Molecular basis for gene-specific transactivation by nuclear receptors.

  2011cited by this paper
• Growth factor stimulation induces a distinct ER(alpha) cistrome underlying breast cancer endocrine resistance.

  2010cited by this paper
• DNA recognition by thyroid hormone and retinoic acid receptors: 3,4,5 rule modified.

  2010cited by this paper
• Structure of a thyroid hormone receptor DNA-binding domain homodimer bound to an inverted palindrome DNA response element.

  2010cited by this paper
• The rules of DNA recognition by the androgen receptor.

  2010cited by this paper
• Minireview: Not picking pockets: nuclear receptor alternate-site modulators (NRAMs).

  2010cited by this paper
• Noncoding RNA Gas5 Is a Growth Arrest– and Starvation-Associated Repressor of the Glucocorticoid Receptor

  2010cited by this paper
• Structural Basis for Cyclic Py-Im Polyamide Allosteric Inhibition of Nuclear Receptor Binding

  2010cited by this paper
• A cooperative and specific DNA-binding mode of HIV-1 integrase depends on the nature of the metallic cofactor and involves the zinc-containing N-terminal domain

  2010cited by this paper
• Understanding the Sequence-Dependence of DNA Groove Dimensions: Implications for DNA Interactions

  2010cited by this paper
• Repression of DNA-binding dependent glucocorticoid receptor-mediated gene expression

  2009cited by this paper
• Allosteric modulation of DNA by small molecules

  2009cited by this paper
• Non-competitive androgen receptor inhibition in vitro and in vivo

  2009cited by this paper
• Cyclic pyrrole-imidazole polyamides targeted to the androgen response element.

  2009cited by this paper
• Interleukin-8 signaling promotes androgen-independent proliferation of prostate cancer cells via induction of androgen receptor expression and activation.

  2008cited by this paper
• Lipoprotein Receptor-1 Attenuates Restenosis of the Artery After Injury Novel Gene Silencer Pyrrole-Imidazole Polyamide Targeting Lectin-Like Oxidized

  2008cited by this paper
• A New Small Molecule Inhibitor of Estrogen Receptor α Binding to Estrogen Response Elements Blocks Estrogen-dependent Growth of Cancer Cells*

  2008cited by this paper
• Structure of the intact PPAR-γ–RXR-α nuclear receptor complex on DNA

  2008cited by this paper
• A global view of transcriptional regulation by nuclear receptors: gene expression, factor localization, and DNA sequence analysis

  2008cited by this paper
• 15-Deoxy-Δ12,14-Prostaglandin J2 Inhibits Transcriptional Activity of Estrogen Receptor-α via Covalent Modification of DNA-Binding Domain

  2007cited by this paper
• Nuclear receptor coregulators: judges, juries, and executioners of cellular regulation.

  2007cited by this paper
• Suppression of androgen receptor-mediated gene expression by a sequence-specific DNA-binding polyamide

  2007cited by this paper
• 15-deoxy-Delta12,14-prostaglandin J2 inhibits transcriptional activity of estrogen receptor-alpha via covalent modification of DNA-binding domain.

  2007cited by this paper
• Indirect readout of DNA sequence by proteins: the roles of DNA sequence-dependent intrinsic and extrinsic forces.

  2006cited by this paper
• Suppression of VEGF transcription in renal cell carcinoma cells by pyrrole-imidazole hairpin polyamides targeting the hypoxia responsive element

  2006cited by this paper
• Disruption of estrogen receptor DNA-binding domain and related intramolecular communication restores tamoxifen sensitivity in resistant breast cancer.

  2006cited by this paper
• Structure of the progesterone receptor-deoxyribonucleic acid complex: novel interactions required for binding to half-site response elements.

  2006cited by this paper
• Predicting protein druggability.

  2005cited by this paper
• Inhibition of DNA binding by human estrogen-related receptor 2 and estrogen receptor alpha with minor groove binding polyamides.

  2005cited by this paper
• The role of the C-terminal extension (CTE) of the estrogen receptor alpha and beta DNA binding domain in DNA binding and interaction with HMGB.

  2004cited by this paper
• Inhibition of vascular endothelial growth factor with a sequence-specific hypoxia response element antagonist.

  2004cited by this paper
• UniProt: the Universal Protein knowledgebase

  2004cited by this paper
• Suppression of breast cancer by chemical modulation of vulnerable zinc fingers in estrogen receptor

  2004cited by this paper
• The Role of the C-terminal Extension (CTE) of the Estrogen Receptor α and β DNA Binding Domain in DNA Binding and Interaction with HMGB*

  2004cited by this paper
• Principles for modulation of the nuclear receptor superfamily

  2004cited by this paper
• Structural insights into regulation of nuclear receptors by ligands

  2003cited by this paper
• Structure of the heterodimeric ecdysone receptor DNA‐binding complex

  2003cited by this paper
• Monomeric complex of human orphan estrogen related receptor-2 with DNA: a pseudo-dimer interface mediates extended half-site recognition.

  2003cited by this paper
• Recognition of the DNA minor groove by pyrrole-imidazole polyamides.

  2003cited by this paper
• Crystallographic analysis of the interaction of the glucocorticoid receptor with DNA

  2003cited by this paper
• Molecular Basis for the Direct Inhibition of AP-1 DNA Binding by 15-Deoxy-Δ12,14-prostaglandin J2*

  2003cited by this paper
• The C-terminal Extension (CTE) of the Nuclear Hormone Receptor DNA Binding Domain Determines Interactions and Functional Response to the HMGB-1/-2 Co-regulatory Proteins*

  2002cited by this paper
• 15-Deoxy-Delta 12,14-prostaglandin J2 inhibition of NF-kappaB-DNA binding through covalent modification of the p50 subunit.

  2001cited by this paper
• Nuclear-receptor interactions on DNA-response elements.

  2001cited by this paper
• DNA deformability as a recognition feature in the reverb response element.

  2001cited by this paper
• 15-Deoxy-Δ12,14-prostaglandin J2Inhibition of NF-κB-DNA Binding through Covalent Modification of the p50 Subunit*

  2001cited by this paper
• Preferential oxidation of zinc finger 2 in estrogen receptor DNA-binding domain prevents dimerization and, hence, DNA binding.

  2000cited by this paper
• Differences in DNA Binding Characteristics of the Androgen and Glucocorticoid Receptors Can Determine Hormone-specific Responses*

  2000cited by this paper
• DNA-binding mechanism of the monomeric orphan nuclear receptor NGFI-B

  1999cited by this paper
• Differential DNA binding by the androgen and glucocorticoid receptors involves the second Zn-finger and a C-terminal extension of the DNA-binding domains.

  1999cited by this paper
• High-resolution solution structure of the retinoid X receptor DNA-binding domain.

  1998cited by this paper
• Structural basis for G•C recognition in the DNA minor groove

  1998cited by this paper
• Inhibition of major-groove-binding proteins by pyrrole-imidazole polyamides with an Arg-Pro-Arg positive patch.

  1998cited by this paper
• Structural elements of an orphan nuclear receptor-DNA complex.

  1998cited by this paper
• Expression of the peroxisome proliferator-activated receptor γ (PPARγ) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein

  1998cited by this paper

• Orphan nuclear receptor transcription factors as drug targets

  2025cites this paper
• Characterization of novel small molecule inhibitors of estrogen receptor-activation function 2 (ER-AF2)

  2024cites this paper
• ERRγ-DBD undergoes dimerization and conformational rearrangement upon binding to the downstream site of the DR1 element.

  2023cites this paper
• [Understanding the Underlying Mechanism of Xenobiotic-Sensing Nuclear Receptor Activation].

  2023cites this paper
• Molecular basis and dual ligand regulation of tetrameric estrogen receptor α/14-3-3ζ protein complex

  2023cites this paper
• Current and emerging approaches to noncompetitive AR inhibition

  2023cites this paper
• Molecular Cloning and Characterization of a Fasciola gigantica Nuclear Receptor Subfamily 1 (FgNR1)

  2022cites this paper
• Evolution of hormone-phenotype couplings and hormone-genome interactions.

  2022cites this paper
• Allosteric binding on nuclear receptors: Insights on screening of non-competitive endocrine-disrupting chemicals.

  2021cites this paper
• TLX, an orphan nuclear receptor with emerging roles in physiology and disease.

  2021cites this paper
• Nuclear receptor crosstalk — defining the mechanisms for therapeutic innovation

  2020cites this paper
• Glucocorticoid receptor activities in the zebrafish model: a review.

  2020cites this paper
• Virtual screening of potentially endocrine-disrupting chemicals against nuclear receptors and its application to identify PPARγ-bound fatty acids

  2020cites this paper
• Nuclear Receptors as Autophagy-Based Antimicrobial Therapeutics

  2020cites this paper
• Molecular Image-Based Prediction Models of Nuclear Receptor Agonists and Antagonists Using the DeepSnap-Deep Learning Approach with the Tox21 10K Library

  2020cites this paper
• Computer-Aided Ligand Discovery for Estrogen Receptor Alpha

  2020cites this paper
• Assessment of the endocrine-disrupting effects of organophosphorus pesticide triazophos and its metabolites on endocrine hormones biosynthesis, transport and receptor binding in silico.

  2019cites this paper
• Editorial for Special Issue on "Alternative nuclear receptor ligands".

  2019cites this paper
• Sex steroids as mediators of phenotypic integration, genetic correlations, and evolutionary transitions.

  2019cites this paper
• Molecular and Cellular Endocrinology

  year unknowncites this paper