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Engineering Orthogonal Ligand−Receptor Pairs from “Near Drugs”
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    Engineering Orthogonal Ligand−Receptor Pairs from “Near Drugs”
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    Contribution from the School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332-0400, and Departments of Pharmacology and Biochemistry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, Texas 75390-9041
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    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 2001, 123, 46, 11367–11371
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    https://doi.org/10.1021/ja0164632
    Published October 20, 2001
    Copyright © 2001 American Chemical Society

    Abstract

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    Cell-permeable small molecules are powerful tools for unraveling complex cellular pathways. We demonstrate that nuclear hormone receptors can be engineered through mutagenesis to create orthogonal ligand−receptor pairs to control transcription. Mutated residues in the retinoid X receptor (RXR) were chosen from structural analysis of RXR and the retinoic acid receptor (RAR) ligand binding domains. The potential ligands screened for activation of variant receptors are “near drugs”compounds synthesized during structure−activity studies that are structurally similar to an approved drug yet inactive on the wild-type receptor. One variant, Q275C;I310M;F313I, is poorly activated by ligands for the wild-type receptor but is activated by a “near drug”, fulfilling the criteria of an orthogonal ligand−receptor pair. These experiments demonstrate that nuclear hormone receptors are well suited to supply orthogonal ligand−receptor pairs for experimental biology, biotechnology, and gene therapy. Our findings also demonstrate the general principle that inactive compounds synthesized during drug discovery can be combined with mutant proteins to rapidly create new tools for controlling cellular processes.

    Copyright © 2001 American Chemical Society

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     Georgia Institute of Technology.

     University of Texas Southwestern Medical Center at Dallas.

    §

     Ligand Pharmaceuticals, Inc., present affiliation Conforma Therapeutics.

     Howard Hughes Medical Institute.

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    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 2001, 123, 46, 11367–11371
    Click to copy citationCitation copied!
    https://doi.org/10.1021/ja0164632
    Published October 20, 2001
    Copyright © 2001 American Chemical Society

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