Show simple item record

dc.contributor.authorEvenseth, Linn M.
dc.contributor.authorKristiansen, Kurt
dc.contributor.authorSong, You
dc.contributor.authorTollefsen, Knut Erik
dc.contributor.authorSylte, Ingebrigt
dc.date.accessioned2019-09-16T11:57:20Z
dc.date.available2019-09-16T11:57:20Z
dc.date.issued2019-06-04
dc.description.abstractMolting 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 <i>Daphnia magna</i> 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. <i>In silico</i> site-directed mutagenesis and MM-GBSA dG calculations revealed that Cys100 (<i>D. magna</i> 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.en_US
dc.description.sponsorshipUiT – The Arctic University of Norwayen_US
dc.descriptionSource at <a href=https://doi.org/10.1016/j.comtox.2019.100091>https://doi.org/10.1016/j.comtox.2019.100091. </a>en_US
dc.identifier.citationEvenseth, L.M., Kristiansen, K., Song, Y., Tollefsen, K.E. & Sylte, I. (2019). <i>In silico</i> site-directed mutagenesis of the <i>Daphnia magna</i> ecdysone receptor identifies critical amino acids for species-specific and inter-species differences in agonist binding. <i>Computational Toxicology, 12</i>, 100091. https://doi.org/10.1016/j.comtox.2019.100091en_US
dc.identifier.cristinIDFRIDAID 1712541
dc.identifier.doi10.1016/j.comtox.2019.100091
dc.identifier.issn2468-1113
dc.identifier.urihttps://hdl.handle.net/10037/16204
dc.language.isoengen_US
dc.publisherElsevieren_US
dc.relation.journalComputational Toxicology
dc.relation.projectIDinfo:eu-repo/grantAgreement/RCN/MILJØFORSK/221455/Norway/Adverse Outcome Pathways for Endocrine Disruption in Daphnia magna, a conceptual approach for mechanistically-based Risk assessment//en_US
dc.rights.accessRightsopenAccessen_US
dc.subjectVDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710en_US
dc.subjectVDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710en_US
dc.subjectEcdysone receptoren_US
dc.subjectDaphnia magnaen_US
dc.subjectHomology modelingen_US
dc.subjectAgonist binding pocketen_US
dc.subjectIn silico mutagenicityen_US
dc.subjectMM-GBSA calculationsen_US
dc.titleIn silico site-directed mutagenesis of the Daphnia magna ecdysone receptor identifies critical amino acids for species-specific and inter-species differences in agonist bindingen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


File(s) in this item

Thumbnail

This item appears in the following collection(s)

Show simple item record