Engineering Orthogonal Ligand−Receptor Pairs from “Near Drugs”Click to copy article linkArticle link copied!
- Donald F. Doyle
- Dwaine A. Braasch
- Laurie K. Jackson
- Harald E. Weiss
- Marcus F. Boehm
- David J. Mangelsdorf
- David R. Corey
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.
*
In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.
†
Georgia Institute of Technology.
‡
University of Texas Southwestern Medical Center at Dallas.
§
Ligand Pharmaceuticals, Inc., present affiliation Conforma Therapeutics.
⊥
Howard Hughes Medical Institute.
Cited By
Smart citations by scite.ai include citation statements extracted from the full text of the citing article. The number of the statements may be higher than the number of citations provided by ACS Publications if one paper cites another multiple times or lower if scite has not yet processed some of the citing articles.
This article is cited by 32 publications.
- Kabirul Islam . Allele-Specific Chemical Genetics: Concept, Strategies, and Applications. ACS Chemical Biology 2015, 10
(2)
, 343-363. https://doi.org/10.1021/cb500651d
- Ki Duk Park, Dongwook Kim, Onrapak Reamtong, Claire Eyers, Simon J. Gaskell, Rihe Liu, and Harold Kohn . Identification of a Lacosamide Binding Protein Using an Affinity Bait and Chemical Reporter Strategy: 14-3-3 ζ. Journal of the American Chemical Society 2011, 133
(29)
, 11320-11330. https://doi.org/10.1021/ja2034156
- Nuska Tschammer, Miriam Dörfler, Harald Hübner and Peter Gmeiner. Engineering a GPCR−Ligand Pair That Simulates the Activation of D2L by Dopamine. ACS Chemical Neuroscience 2010, 1
(1)
, 25-35. https://doi.org/10.1021/cn900001b
- Aleksandra Filipovska and Oliver Rackham . Building a Parallel Metabolism within the Cell. ACS Chemical Biology 2008, 3
(1)
, 51-63. https://doi.org/10.1021/cb700185e
- Jonathan D.M. Helander, Aditya S. Vaidya, Sean R. Cutler. Chemical manipulation of plant water use. Bioorganic & Medicinal Chemistry 2016, 24
(3)
, 493-500. https://doi.org/10.1016/j.bmc.2015.11.010
- Martin Kavšček, Martin Stražar, Tomaž Curk, Klaus Natter, Uroš Petrovič. Yeast as a cell factory: current state and perspectives. Microbial Cell Factories 2015, 14
(1)
https://doi.org/10.1186/s12934-015-0281-x
- David E. Cook, Carl H. Mesarich, Bart P.H.J. Thomma. Understanding Plant Immunity as a Surveillance System to Detect Invasion. Annual Review of Phytopathology 2015, 53
(1)
, 541-563. https://doi.org/10.1146/annurev-phyto-080614-120114
- DeBin Ji, Lei Wang, WuJun Liu, ShuHua Hou, K. ZongBao Zhao. Synthesis of NAD analogs to develop bioorthogonal redox system. Science China Chemistry 2013, 56
(3)
, 296-300. https://doi.org/10.1007/s11426-012-4815-3
- Grace Jones, Peter Teal, Vincent C. Henrich, Anna Krzywonos, Agnes Sapa, Mietek Wozniak, John Smolka, Davy Jones. Ligand binding pocket function of Drosophila USP is necessary for metamorphosis. General and Comparative Endocrinology 2013, 182 , 73-82. https://doi.org/10.1016/j.ygcen.2012.11.009
- Hally Anne Shaffer, Michael Kenneth Rood, Badar Kashlan, Eileen I-ling Chang, Donald Francis Doyle, Bahareh Azizi. BAPJ69-4A: A yeast two-hybrid strain for both positive and negative genetic selection. Journal of Microbiological Methods 2012, 91
(1)
, 22-29. https://doi.org/10.1016/j.mimet.2012.07.003
- Giora Ben-Ari. The ABA signal transduction mechanism in commercial crops: learning from Arabidopsis. Plant Cell Reports 2012, 31
(8)
, 1357-1369. https://doi.org/10.1007/s00299-012-1292-2
- Joseph A. Gredell, Christopher S. Frei, Patrick C. Cirino. Protein and RNA engineering to customize microbial molecular reporting. Biotechnology Journal 2012, 7
(4)
, 477-499. https://doi.org/10.1002/biot.201100266
- Matthias Rabiller, Jeffrey R. Simard, Daniel Rauh. Dissecting Phosphorylation Networks: The Use of Analogue‐Sensitive Kinases and More Specific Kinase Inhibitors as Tools. 2011, 69-83. https://doi.org/10.1002/9783527633470.ch3
- Jennifer L Taylor, Priyanka Rohatgi, H Trent Spencer, Donald F Doyle, Bahareh Azizi. Characterization of a molecular switch system that regulates gene expression in mammalian cells through a small molecule. BMC Biotechnology 2010, 10
(1)
https://doi.org/10.1186/1472-6750-10-15
- Igor Usai, Marcus Krueger, Jürgen Einsiedel, Wolfgang Hillen, Peter Gmeiner. Click‐Chemistry‐Derived Tetracycline–Amino Acid Conjugates Exhibiting Exceptional Potency and Exclusive Recognition of the Reverse Tet Repressor. ChemBioChem 2010, 11
(5)
, 703-712. https://doi.org/10.1002/cbic.200900710
- Christian Kormann, Irina Pimenta, Stefan Löber, Cornelius Wimmer, Harald Lanig, Timothy Clark, Wolfgang Hillen, Peter Gmeiner. Diarylpropane‐1,3‐dione Derivatives as TetR‐Inducing Tetracycline Mimetics: Synthesis and Biological Investigations. ChemBioChem 2009, 10
(18)
, 2924-2933. https://doi.org/10.1002/cbic.200900564
- Konstantin Levitsky, Paul Szymanski, Fang Jin, Janet A. Meurer-Ogden, Richard N. Harkins. Development and Validation of an Improved Inducer–Regulator Protein Complex in the pBRES-Regulated Expression System. Human Gene Therapy 2008, 19
(11)
, 1273-1282. https://doi.org/10.1089/hum.2008.082
- James Inglese, Douglas S. Auld. High Throughput Screening (
HTS
) Techniques: Applications in Chemical Biology. 2008, 1-15. https://doi.org/10.1002/9780470048672.wecb223
- John T. Koh. Engineering Control Over Protein Function; Transcription Control by Small Molecules. 2007, 174-197. https://doi.org/10.1002/9783527619375.ch3c
- John B Biggins, John T Koh. Chemical biology of steroid and nuclear hormone receptors. Current Opinion in Chemical Biology 2007, 11
(1)
, 99-110. https://doi.org/10.1016/j.cbpa.2006.10.042
- F.C. Acher. Orthogonal Ligand–Receptor Pairs. 2007, 215-234. https://doi.org/10.1016/B0-08-045044-X/00084-5
- Paola Gallinari, Armin Lahm, Uwe Koch, Chantal Paolini, Maria Chiara Nardi, Giuseppe Roscilli, Olaf Kinzel, Daniela Fattori, Ester Muraglia, Carlo Toniatti, Riccardo Cortese, Raffaele De Francesco, Gennaro Ciliberto. A Functionally Orthogonal Estrogen Receptor-Based Transcription Switch Specifically Induced by a Nonsteroid Synthetic Ligand. Chemistry & Biology 2005, 12
(8)
, 883-893. https://doi.org/10.1016/j.chembiol.2005.05.018
- Karuppiah Chockalingam, Huimin Zhao. Creating new specific ligand–receptor pairs for transgene regulation. Trends in Biotechnology 2005, 23
(7)
, 333-335. https://doi.org/10.1016/j.tibtech.2005.05.002
- Karuppiah Chockalingam, Zhilei Chen, John A. Katzenellenbogen, Huimin Zhao. Directed evolution of specific receptor–ligand pairs for use in the creation of gene switches. Proceedings of the National Academy of Sciences 2005, 102
(16)
, 5691-5696. https://doi.org/10.1073/pnas.0409206102
- Lauren J. Schwimmer, Priyanka Rohatgi, Bahareh Azizi, Katherine L. Seley, Donald F. Doyle. Creation and discovery of ligand–receptor pairs for transcriptional control with small molecules. Proceedings of the National Academy of Sciences 2004, 101
(41)
, 14707-14712. https://doi.org/10.1073/pnas.0400884101
- Axel Jacobi von Wangelin, Mathias U. Frederiksen. Zinc‐Mediated Reactions. 2004, 519-551. https://doi.org/10.1002/9783527619405.ch3g
- John T. Koh, Marc C. Putnam. Towards the Rational Design of Hormone Analogs Which Complement Receptor Mutations. 2004, 119-136. https://doi.org/10.1007/978-1-4020-7852-1_8
- Bahareh Azizi, Eileen I Chang, Donald F Doyle. Chemical complementation: small-molecule-based genetic selection in yeast. Biochemical and Biophysical Research Communications 2003, 306
(3)
, 774-780. https://doi.org/10.1016/S0006-291X(03)01039-8
- Colin M Tice, Robert E Hormann, Christine S Thompson, Jennifer L Friz, Caitlin K Cavanaugh, Enrique L Michelotti, Javier Garcia, Ernesto Nicolas, Fernando Albericio. Synthesis and SAR of α-Acylaminoketone ligands for control of gene expression. Bioorganic & Medicinal Chemistry Letters 2003, 13
(3)
, 475-478. https://doi.org/10.1016/S0960-894X(02)00980-0
- Hikari A.I. Yoshihara, Ngoc-Ha Nguyen, Thomas S. Scanlan. Design and Synthesis of Receptor Ligands. 2003, 71-91. https://doi.org/10.1016/S0076-6879(03)64005-X
- Blake R. Peterson. Augmenting Vitamin D to Combat Genetic Disease. Chemistry & Biology 2002, 9
(12)
, 1265-1266. https://doi.org/10.1016/S1074-5521(02)00287-9
- Lloyd D Graham. Ecdysone-controlled expression of transgenes. Expert Opinion on Biological Therapy 2002, 2
(5)
, 525-535. https://doi.org/10.1517/14712598.2.5.525
Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.
Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.
The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.