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Research ArticleMinireview

Small Molecule Modulation of Nuclear Receptor Conformational Dynamics: Implications for Function and Drug Discovery

Douglas J. Kojetin and Thomas P. Burris
Molecular Pharmacology January 2013, 83 (1) 1-8; DOI: https://doi.org/10.1124/mol.112.079285
Douglas J. Kojetin
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida
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Thomas P. Burris
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida
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Abstract

Nuclear receptors are targets for a wide range of ligands, both natural and synthetic, that regulate their activity and provide a means to pharmacologically modulate the receptor. Recent emphasis in the nuclear receptor field has focused on selective nuclear receptor modulators, which can display graded transcriptional responses and tissue selective pharmacological responses that deviate from the prototypical agonist or antagonist. Understanding the molecular mechanism of action of these selective modulators will provide significant insight toward the development of the next generation of modulators. Although most nuclear receptor structural studies have primarily focused on obtaining ligand-receptor cocrystal structures, recent studies implicate an important role for protein dynamics in the mechanism of action of nuclear receptor ligands. Here we review nuclear receptor studies reporting how ligands modulate the conformational dynamics of the nuclear receptor ligand-binding domain (LBD). A particular emphasis is placed on protein NMR and hydrogen/deuterium exchange (HDX) techniques and how they provide complementary information that, when combined with crystallography, provide detailed insight into the function of nuclear receptors.

Footnotes

  • dx.doi.org/10.1124/mol.112.079285.

  • This work was supported by the James and Esther King Biomedical Research Program through the Florida Department of Health [Grant 1KN-09]; the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01-DK080201]; and the National Institutes of Health National Institute of Mental Health [Grants R01-MH092769 and R01-MH093429].

  • Received April 12, 2012.
  • Accepted August 6, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 83 (1)
Molecular Pharmacology
Vol. 83, Issue 1
1 Jan 2013
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Research ArticleMinireview

Ligand Modulation of NR Conformational Dynamics

Douglas J. Kojetin and Thomas P. Burris
Molecular Pharmacology January 1, 2013, 83 (1) 1-8; DOI: https://doi.org/10.1124/mol.112.079285

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Research ArticleMinireview

Ligand Modulation of NR Conformational Dynamics

Douglas J. Kojetin and Thomas P. Burris
Molecular Pharmacology January 1, 2013, 83 (1) 1-8; DOI: https://doi.org/10.1124/mol.112.079285
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  • Article
    • Abstract
    • Introduction
    • Ligand-Receptor Crystal Structures and the Helix 12 Structure-Function Model
    • Ligand Stabilization of LBD Conformational Dynamics
    • Dynamic Features of Graded Receptor Agonism
    • Conformational Dynamics as a Guide for Nuclear Receptor Drug Discovery
    • Summary
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