In silico site-directed mutagenesis of the Daphnia magna ecdysone receptor identifies critical amino acids for species-specific and inter-species differences in agonist binding
| Autor: | Ingebrigt Sylte, You Song, Knut Erik Tollefsen, Kurt Kristiansen, Linn Samira Mari Evenseth |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Agonist
medicine.drug_class Health Toxicology and Mutagenesis In silico Daphnia magna 010501 environmental sciences Toxicology 01 natural sciences 03 medical and health sciences MM-GBSA calculations medicine Agonist binding pocket Homology modeling Site-directed mutagenesis 030304 developmental biology 0105 earth and related environmental sciences chemistry.chemical_classification 0303 health sciences biology Ecdysone receptor Mutagenesis fungi VDP::Medisinske Fag: 700::Basale medisinske odontologiske og veterinærmedisinske fag: 710 biology.organism_classification VDP::Medical disciplines: 700::Basic medical dental and veterinary science disciplines: 710 Computer Science Applications Amino acid In silico mutagenicity chemistry Biochemistry hormones hormone substitutes and hormone antagonists |
| Zdroj: | Computational Toxicology |
| Popis: | Source at https://doi.org/10.1016/j.comtox.2019.100091. Molting is an essential process in the life cycle of arthropods and is regulated by complex neuroendocrine pathways where activation of the ecdysone receptor (EcR) plays a major role. The EcR forms a non-covalent heterodimer with the ultraspiracle protein (USP) when activated by endogenous ecdysteroids, but can also be activated by several insecticides and other environmental chemicals. Environmental release of exogenous chemicals may thus represent a risk to non-target species due to phylogenetic conservation of the EcR in arthropods. In the present study, structural analysis and homology models of the EcR from the freshwater crustacean Daphnia magna were used to characterise the agonist binding pocket and identify amino acids responsible for differences in agonist binding between arthropod species. The analysis showed that the binding pockets of steroidal and non-steroidal agonists are partly overlapping, and the phylogenetically conserved Thr59 is a key residue for binding both types of agonists. In silico site-directed mutagenesis and MM-GBSA dG calculations revealed that Cys100 (D. magna numbering) is a structural determinant for cross species affinities. Other determinants are Val129 for both types of agonists, Thr132 for steroidal agonists and Asp134 for non-steroidal agonists. The present results can be used to predict cross species sensitivity for EcR agonists, and shows that homology modelling and affinity predictions may contribute to identifying susceptible species for EcR-mediated endocrine disruption. |
| Databáze: | OpenAIRE |
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