Ecdysteroid ligand-receptor selectivity–exploring trends to design orthogonal gene switches
Abstract
A set of thirty-two natural and ten semisynthetic ecdysteroids was assayed in murine 3T3 cells across ten different ecdysteroid receptor (EcR) ligand-binding domains derived from nine arthropod species in an engineered gene switch format. Among the ecdysteroids tested, the most biologically widespread ecdysteroid, 20-hydroxyecdysone (20E), was moderately and consistently potent across the tested EcRs. The most potent ligand-receptor combination (EC(50) = 0.3 nm) was ponasterone A (PoA) actuating the Nephotettix cincticeps EcR switch. The most robust ligand-receptor combination, as measured by potency and efficacy, was PoA actuating either the Bombyx mori EcR or a 'VY' (E274V/V390I/Y410E) mutant of Choristoneura fumiferana EcR. Parallel ecdysteroid structure-activity relationships were observed across species; addition of hydroxyl groups at positions 2, 3, 14, 20 and 22 incrementally enhanced potency, whereas hydroxylation at position 25 retarded potency. Nevertheless, several outlier ligand-EcR combinations, such as cyasterone actuating the VY C. fumiferana EcR mutant and canescensterone activating Bemisia argentifolii EcR, exhibited an inversion of relative potency, and therefore lend themselves to construction of orthogonal duplex gene switches. The potency inversion between these two ligand-receptor pairs can be accounted for by steroid-tail contact residues Tyr411 and Met502 in VY C. fumiferana EcR corresponding to two threonines in B. argentifolii EcR. Another potency inversion was also observed with cyasterone operating on the VY mutant of C. fumiferana EcR and polypodine B activating Aedes aegypti EcR. The ecdysteroid-EcR dataset, generated in a non-natural system, nevertheless invites conjecture regarding relative ecdysteroid potencies, plant species distribution of certain phytoecdysteroids, and the role of phytoecdysteroids as chemodefense against relevant insect herbivores.
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Beta-ecdysone binds to ecdysone receptor with EC50 of 0.3 nM, a ligand-activated transcriptional factor found in arthropods.
“βEcd binds to ecdysone receptor with EC50 of 0.3nm, a ligand-activated transcriptional factor found in arthropods [62, 63].”
From Prevention of glucocorticoid induced bone changes with beta-ecdysone (2015) · cites this paper as [63]
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Self-citation
- Authors
- Lapenna, S., Friz, J., Barlow, A., Palli, S. R., Dinan, L., & Hormann, R. E.
- Affiliations
- University of Exeter (GB)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- University of Kentucky (US)
- Centre National de la Recherche Scientifique (FR)
- Venue
- The FEBS Journal
- Publisher
- Wiley
- Published
- 2008-11-11
- Volume
- 275
- Issue
- 23
- Pages
- 5785-5809
- ISSN
- 1742-464X (ISSN-L)
- 1742-4658
- OpenAlex
- W1586088785
- Cited by
- 15
- References
- 75
- Citations by year
- 2026: 1 · 2022: 2 · 2021: 1 · 2015: 1 · 2014: 1 · 2013: 1 · 2012: 2
- FWCI
- 1.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- FEBS Journal (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Keywords
- ecdysteroid receptor, ligand-binding domain, 20-hydroxyecdysone, ponasterone A, structure-activity relationship, receptor mutants, Bombyx mori, spruce budworm, Bemisia argentifolii, Aedes aegypti, phytoecdysteroids, 3T3 fibroblasts
- MeSH terms
- Amino Acid Sequence, Animals, Arthropods, Binding Sites, Binding, Competitive, Ligands, Luciferases, Models, Molecular, Molecular Sequence Data, Protein Conformation, Receptors, Steroid, Recombinant Fusion Proteins, Structure-Activity Relationship, Transfection, Molecular Structure, Sequence Homology, Amino Acid, Protein Structure, Tertiary, Amino Acid Substitution, Two-Hybrid System Techniques, Ecdysteroids, NIH 3T3 Cells, Mice
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