Principles for modulation of the nuclear receptor superfamily

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Nuclear receptors are major targets for drug discovery and have key roles in development and homeostasis, as well as in many diseases such as obesity, diabetes and cancer. This review provides a general overview of the mechanism of action of nuclear receptors and explores the various factors that are instrumental in modulating their pharmacology. In most cases, the response of a given receptor to a particular ligand in a specific tissue will be dictated by the set of proteins with which the receptor is able to interact. One of the most promising aspects of nuclear receptor pharmacology is that it is now possible to develop ligands with a large spectrum of full, partial or inverse agonist or antagonist activities, but also compounds, called selective nuclear receptor modulators, that activate only a subset of the functions induced by the cognate ligand or that act in a cell-type-selective manner.

Key Points

  • Many factors have a role in defining the pharmacological profile of the nuclear receptor family of drug targets.

  • The response to a given ligand will be dictated by the set of proteins (from DNA-binding partners to transcriptional coregulators and transcription factors involved in crosstalk) with which this receptor will interact.

  • The potential of developing new ligands with tissue-specific and/or promoter-specific activities, called selective nuclear receptor modulators (SNuRMs), is becoming an attractive prospect for drug discovery.

  • Consideration of the evolution of nuclear receptors and developing an established nomenclature system should aid our understanding of the complex pharmacology of this receptor superfamily.

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Figure 1: Nuclear receptors in action.
Figure 2: Ligand binding induces a conformational change of the ligand-binding domain structure of nuclear receptors.
Figure 3: Comparative view of the ligand-binding pockets of the oestrogen receptor-α and -β.
Figure 4: Structural basis of antagonist action.

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V.L. thanks S. Watson, J. Samarut and M. Schubert for critical reading of the manuscript as well as H. Escriva and J. Katzenellenbogen for help in preparation. H.G. would like to thank the members of his and D. Moras' lab for discussions and figures. J.-Å.G. also thanks K. Koehler for discussions and for figures. Work in our laboratories is supported by grants from the Association for International Cancer Research, the Association pour la Recherche contre le Cancer, the Fondation de France, the European Community, Bristol-Myers Squibb, The Swedish Cancer Fund, The Swedish Science Council, KaroBio AB, Centre National de la Recherche Scientifique, Ministère de la Recherche et de la Technologie, and Région Rhône-Alpes. This publication is supported by the CASCADE network of excellence of the European Community.

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A ligand that stabilizes an inactive conformation of a receptor — for example, by increasing corepressor interaction, thereby decreasing signalling below basal levels.


(SNuRMS). Ligands that selectively modulate different receptor subtypes and/or act in a cell-selective manner.


Action of a ligand that does not involve the activation of the target genes of its cognate receptor.


Activation of transcription by the binding of a transcription factor to a DNA regulatory sequence.


The creation of a new compound with similar biological properties to the parent compound by exchanging an atom or a group of atoms with another, broadly similar atom or group of atoms.


A side effect that occurs in 10–15% of patients that is preceded by increasing leukocyte count and that includes fever, respiratory distress, weight gain and oedema of the lower extremities and which is fatal in at least 10% of cases.


A chronic lymphoproliferative disease of the skin.


Repression of transcription through a mechanism in which a transcriptional activator, such as a nuclear receptor, represses the transcriptional activation potential of another transactivator, such as AP1, without binding to DNA or altering the DNA-binding activity of AP1. Several mechanisms have been proposed (see text), but none explains all of the experimental observations.


Protein-based recognition agents that block protein–protein interactions.

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Gronemeyer, H., Gustafsson, J. & Laudet, V. Principles for modulation of the nuclear receptor superfamily. Nat Rev Drug Discov 3, 950–964 (2004) doi:10.1038/nrd1551

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