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Molecular Pharmacology

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Research ArticleMini Special Section—Structural Basis of Receptor-Ligand Interactions

Structural Analysis of the Glucocorticoid Receptor Ligand-Binding Domain in Complex with Triamcinolone Acetonide and a Fragment of the Atypical Coregulator, Small Heterodimer Partner

Emily R. Weikum, C. Denise Okafor, Emma H. D’Agostino, Jennifer K. Colucci and Eric A. Ortlund
Molecular Pharmacology July 2017, 92 (1) 12-21; DOI: https://doi.org/10.1124/mol.117.108506
Emily R. Weikum
Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia
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C. Denise Okafor
Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia
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Emma H. D’Agostino
Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia
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Jennifer K. Colucci
Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia
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Eric A. Ortlund
Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia
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Abstract

The synthetic glucocorticoids (GCs) dexamethasone, mometasone furoate, and triamcinolone acetonide are pharmaceutical mainstays to treat chronic inflammatory diseases. These drugs bind to the glucocorticoid receptor (GR), a ligand-activated transcription factor and member of the nuclear receptor superfamily. The GR is widely recognized as a therapeutic target for its ability to counter proinflammatory signaling. Despite the popularity of GCs in the clinic, long-term use leads to numerous side effects, driving the need for new and improved drugs with less off-target pharmacology. X-ray crystal structures have played an important role in the drug-design process, permitting the characterization of robust structure-function relationships. However, steroid receptor ligand-binding domains (LBDs) are inherently unstable, and their crystallization requires extensive mutagenesis to enhance expression and crystallization. Here, we use an ancestral variant of GR as a tool to generate a high-resolution crystal structure of GR in complex with the potent glucocorticoid triamcinolone acetonide (TA) and a fragment of the small heterodimer partner (SHP). Using structural analysis, molecular dynamics, and biochemistry, we show that TA increases intramolecular contacts within the LBD to drive affinity and enhance stability of the receptor-ligand complex. These data support the emerging theme that ligand-induced receptor conformational dynamics at the mouth of the pocket play a major role in steroid receptor activation. This work also represents the first GR structure in complex with SHP, which has been suggested to play a role in modulating hepatic GR function.

Footnotes

    • Received February 1, 2017.
    • Accepted April 6, 2017.
  • E.R.W. is supported by a predoctoral NRSA awarded by the National Institutes of Health General Medical Sciences [Grant 1F31GM113397-01A1]. E.A.O. is supported by the National Institutes of Health [Grant R01DK095750], American Heart Association [Grant 14GRNT20460124], and a W. M. Keck Foundation Medical Research Grant. C.D.O. is funded by a National Institutes of Health General Medical Sciences Institutional Research and Career Development Award [Grant K12 GM000680].

  • https://doi.org/10.1124/mol.117.108506.

  • Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 92 (1)
Molecular Pharmacology
Vol. 92, Issue 1
1 Jul 2017
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Research ArticleMini Special Section—Structural Basis of Receptor-Ligand Interactions

Novel Glucocorticoid Receptor-Ligand Structure

Emily R. Weikum, C. Denise Okafor, Emma H. D’Agostino, Jennifer K. Colucci and Eric A. Ortlund
Molecular Pharmacology July 1, 2017, 92 (1) 12-21; DOI: https://doi.org/10.1124/mol.117.108506

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Research ArticleMini Special Section—Structural Basis of Receptor-Ligand Interactions

Novel Glucocorticoid Receptor-Ligand Structure

Emily R. Weikum, C. Denise Okafor, Emma H. D’Agostino, Jennifer K. Colucci and Eric A. Ortlund
Molecular Pharmacology July 1, 2017, 92 (1) 12-21; DOI: https://doi.org/10.1124/mol.117.108506
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