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Inverse agonists and antagonists of retinoid receptors
William Bourguet1, Angel R de Lera, Hinrich Gronemeyer
1INSERM U554 and CNRS UMR5048, Centre de Biochimie Structurale, Universités Montpellier 1 & 2, Montpellier, France.
Abstract:
Nuclear receptors (NRs) are ligand-inducible transcription factors that regulate a plethora of cell biological phenomena, thus orchestrating complex events like development, organ homeostasis, immune function, and reproduction. Due to their regulatory potential, NRs are major drug targets for a variety of diseases, including cancer and metabolic diseases, and had a major societal impact following the development of contraceptives and abortifacients. Not surprisingly in view of this medical and societal importance, a large amount of diverse NR ligands have been generated and the corresponding structural and functional analyses have provided a deep insight into the molecular basis of ligand action. What we have learnt is that ligands regulate, via allosteric conformational changes, the ability of NRs to interact with different sets of coregulators which in turn recruit enzymatically active complexes, the workhorses of the ligand-induced epigenetic and transcription-regulatory events. Thus, ligands essentially direct the communication of a given NR with its intracellular environment at the chromatin and extragenomic level to modulate gene programs directly at the chromatin level or via less well-understood extranuclear actions. Here we will review our current structural and mechanistic insight into the functionalities of subsets of retinoid and rexinoid ligands that act generically as antagonists but follow different mechanistic principles, resulting in "classical" or neutral antagonism, or inverse agonism. In addition, we describe the chemical features and guidelines for the synthesis of retinoids/rexinoids that exert specific functions and we provide protocols for a number of experimental approaches that are useful for studies of the agonistic and antagonistic features of NR ligands.
Insights
Nuclear receptors (NRs) are key transcription factors regulating cell functions. Ligands modulate NR activity, impacting gene expression and disease treatment, with specific retinoid and rexinoid insights reviewed.
Area of Science:
- Molecular Biology
- Endocrinology
- Pharmacology
Background:
- Nuclear receptors (NRs) are crucial ligand-inducible transcription factors governing development, homeostasis, immunity, and reproduction.
- Their role in diseases like cancer and metabolic disorders makes them significant drug targets, with notable societal impact from contraceptives.
- Extensive research has elucidated the molecular mechanisms of NR-ligand interactions and their downstream effects.
Purpose of the Study:
- To review structural and mechanistic insights into retinoid and rexinoid ligand functionalities.
- To explore how these ligands act as antagonists through distinct mechanisms, including classical antagonism, neutral antagonism, and inverse agonism.
- To describe chemical features, synthesis guidelines, and experimental protocols for studying NR ligand activity.
Main Methods:
- Structural and functional analyses of nuclear receptor-ligand interactions.
- Mechanistic studies on retinoid and rexinoid antagonism (classical, neutral, inverse agonism).
- Chemical synthesis of specific retinoid/rexinoid ligands.
- Development of experimental protocols for assessing agonistic and antagonistic NR ligand features.
Main Results:
- Ligands induce allosteric conformational changes in NRs, altering coregulator interactions and epigenetic modifications.
- Retinoid and rexinoid ligands exhibit diverse antagonistic mechanisms, leading to distinct functional outcomes.
- Specific chemical features and synthesis strategies enable the design of retinoids/rexinoids with tailored functions.
Conclusions:
- Ligand binding is central to NR function, dictating interactions with coregulators and modulating gene expression.
- Understanding the nuanced mechanisms of retinoid and rexinoid antagonism is critical for drug development.
- This review provides a comprehensive resource for studying NR ligand action, aiding future therapeutic strategies.
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