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Species differences in ligand interaction and activation of estrogen receptors in fish and human
Örebro University, School of Science and Technology. (Biology, The Life Science Center)
Örebro University, School of Science and Technology. (Biology, The Life Science Center)
Örebro University, School of Science and Technology. (Biology, The Life Science Center)ORCID iD: 0000-0001-7336-6335
2019 (English)In: Journal of Steroid Biochemistry and Molecular Biology, ISSN 0960-0760, E-ISSN 1879-1220, article id 105450Article in journal (Refereed) Epub ahead of print
Abstract [en]

Estrogen receptor (ER) sequences vary between species and this suggests that there are differences in the ligand-specificity, leading to species-specific effects. This would indicate that it is not possible to generalize effects across species. In this study, we investigated the differences in activation potencies and binding affinities of ER´s alpha (α) and beta (β) in human, zebrafish and sea bream to elucidate species differences in response to estradiol, estrone, estriol and methyltestosterone. In vitro analysis showed that estradiol had the highest activity for all the ER´s except for human ERβ and seabream ERβ2. Alignment of the ligand binding domain and ligand binding pocket (LBP) residues of the three species showed that different residues were involved in the LBPs which led to differences in pocket volume, affected binding affinity and orientation of the ligands. By combining in silico and in vitro results, it was possible to identify the ligand specificities of ER´s. The results demonstrated that the human ER´s show lower resolution in ligand-dependent activation, suggesting higher promiscuity, than the zebrafish and seabream ER´s. These results show species-specificity of ER´s and suggest that species-specific differences must be taken into consideration when studying different exposure scenarios.

Place, publisher, year, edition, pages
Pergamon Press, 2019. article id 105450
Keywords [en]
In silico, ligand binding pocket, ligand resolution, ligand specificity, species-specific
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:oru:diva-75906DOI: 10.1016/j.jsbmb.2019.105450PubMedID: 31437548OAI: oai:DiVA.org:oru-75906DiVA, id: diva2:1349544
Available from: 2019-09-09 Created: 2019-09-09 Last updated: 2019-09-09Bibliographically approved

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Asnake, SolomonModig, CarinaOlsson, Per-Erik

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