Engineering orthogonal ligand-receptor pairs from "near drugs"

D. F. Doyle, D. A. Braasch, L. K. Jackson, H. E. Weiss, M. F. Boehm, D. J. Mangelsdorf, D. R. Corey

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)11367-11371
Number of pages5
JournalJournal of the American Chemical Society
Volume123
Issue number46
DOIs
StatePublished - Nov 21 2001

Fingerprint

Ligands
Pharmaceutical Preparations
Retinoid X Receptors
Cytoplasmic and Nuclear Receptors
Drug Receptors
Gene therapy
Mutagenesis
Retinoic Acid Receptors
Mutant Proteins
Drug Discovery
Transcription
Biotechnology
Structural analysis
Genetic Therapy
Chemical activation
Proteins
Molecules
Acids
Experiments

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Engineering orthogonal ligand-receptor pairs from "near drugs". / Doyle, D. F.; Braasch, D. A.; Jackson, L. K.; Weiss, H. E.; Boehm, M. F.; Mangelsdorf, D. J.; Corey, D. R.

In: Journal of the American Chemical Society, Vol. 123, No. 46, 21.11.2001, p. 11367-11371.

Research output: Contribution to journalArticle

Doyle, D. F. ; Braasch, D. A. ; Jackson, L. K. ; Weiss, H. E. ; Boehm, M. F. ; Mangelsdorf, D. J. ; Corey, D. R. / Engineering orthogonal ligand-receptor pairs from "near drugs". In: Journal of the American Chemical Society. 2001 ; Vol. 123, No. 46. pp. 11367-11371.
@article{60f7571eeba64fb99e897608aa35ed52,
title = "Engineering orthogonal ligand-receptor pairs from {"}near drugs{"}",
abstract = "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.",
author = "Doyle, {D. F.} and Braasch, {D. A.} and Jackson, {L. K.} and Weiss, {H. E.} and Boehm, {M. F.} and Mangelsdorf, {D. J.} and Corey, {D. R.}",
year = "2001",
month = "11",
day = "21",
doi = "10.1021/ja0164632",
language = "English (US)",
volume = "123",
pages = "11367--11371",
journal = "Journal of the American Chemical Society",
issn = "0002-7863",
publisher = "American Chemical Society",
number = "46",

}

TY - JOUR

T1 - Engineering orthogonal ligand-receptor pairs from "near drugs"

AU - Doyle, D. F.

AU - Braasch, D. A.

AU - Jackson, L. K.

AU - Weiss, H. E.

AU - Boehm, M. F.

AU - Mangelsdorf, D. J.

AU - Corey, D. R.

PY - 2001/11/21

Y1 - 2001/11/21

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0035930028&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035930028&partnerID=8YFLogxK

U2 - 10.1021/ja0164632

DO - 10.1021/ja0164632

M3 - Article

VL - 123

SP - 11367

EP - 11371

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

SN - 0002-7863

IS - 46

ER -