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Thinking Outside the Box: Alternative Binding Sites in the Ligand Binding Domain of Nuclear Receptors

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Nuclear Receptors: From Structure to the Clinic

Abstract

Throughout the past years nuclear receptors (NRs) have been pharmaceutical targets for many diseases, such as cancers and metabolic diseases, due to the physiological spectrum of different cell regulation mechanisms that involve their actions e.g. cell proliferation, metabolism and homeostasis. The initial scientific focus for drug discovery in NRs has resulted in many important anticancer drugs currently available in the clinic. Yet, despite these successes the therapeutic strategy undertaken has almost exclusively focused in targeting their ligand binding pocket (LBP). However, the versatile nature of these proteins has shown the development of drug resistance to these drugs through mechanisms such as mutations in the LBP, which render antagonistic inhibitors as agonists and exacerbate disease progression. The need for new clinical antagonists with alternative mechanisms of actions has led the scientific community to explore other alternative sites such as druggable non-ligand binding pockets (non-LBPs). Here we will cover the available non-LBPs of different NRs and the current results that identify these sites as valuable druggable targeting pockets that may lead to alternative therapeutic strategies.

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Acknowledgements

We are very grateful to Medivation for a research sponsorphip and the Bayer Pharma AG initiative “From Targets to Novel Drugs” Grants4Targets support (2012-05-0708), for the Plan Nacional I + D+i: SAF-2011-29681 Fellowship (MINECO, Gobierno de España).

Table 1 List of inhibitors that have been proven to bind to NRs alternative sites. The list includes the chemical structure of each inhibitor, in which pocket they bind to the NR, if there is a crystal structure and if so the Protein Data Bank (PDB) number as well as the activity these inhibitors have shown and where they have been published
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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona (UB), Baldiri-Reixac 15–21, 08028, Barcelona, Spain

    Nerea Gallastegui & Eva Estébanez-Perpiñá

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  1. Nerea Gallastegui
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  2. Eva Estébanez-Perpiñá
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Correspondence to Eva Estébanez-Perpiñá .

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Editors and Affiliations

  1. School of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom

    Iain J. McEwan

  2. Department of Basic Sciences, The Commonwealth Medical College, Scranton, Pennsylvania, USA

    Raj Kumar

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Gallastegui, N., Estébanez-Perpiñá, E. (2015). Thinking Outside the Box: Alternative Binding Sites in the Ligand Binding Domain of Nuclear Receptors. In: McEwan, I., Kumar, R. (eds) Nuclear Receptors: From Structure to the Clinic. Springer, Cham. https://doi.org/10.1007/978-3-319-18729-7_10

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