0603119 - ÚMG 2026 RIV NL eng J - Článek v odborném periodiku
Sedlák, David - Tůma, R. - Kolla, Jayaprakash Narayana - Mokhamatam, Raveendra Babu - Bahrová, Liliia - Lisová, Michaela - Bittová, Lenka - Jindra, Marek
Unique and Common Agonists Act the Insect Juvenile Hormone Rece and the Human AHR.
Journal of Molecular Biology. Roč. 437, č. 2 (2025), č. článku 168883. ISSN 0022-2836. E-ISSN 1089-8638
Grant CEP: GA ČR(CZ) GX20-05151X; GA MŠMT(CZ) LM2018130
Institucionální podpora: RVO:68378050 ; RVO:60077344
Klíčová slova: aryl-hydrocarbon receptor * molecular-dynamics * nuclear receptors * protein * modulation * activation * disruptors * tryptophan * endocrine * homology
Obor OECD: Biochemistry and molecular biology; Developmental biology (BC-A)
Impakt faktor: 4.7, rok: 2023 ; AIS: 1.896, rok: 2023
Způsob publikování: Open access
Web výsledku:
https://www.sciencedirect.com/science/article/abs/pii/S0022283624005138?via%3DihubDOI: https://doi.org/10.1016/j.jmb.2024.168883

Transcription factors of the bHLH-PAS family play vital roles in animal development, physiology, and disease. Two members of the family require binding of low-molecular weight ligands for their activity: the vertebrate aryl hydrocarbon receptor (AHR) and the insect juvenile hormone receptor (JHR). In the fly Drosophila melanogaster, the paralogous proteins GCE and MET constitute the ligand-binding component of JHR complexes. Whilst GCE/MET and AHR are phylogenetically heterologous, their mode of action is similar. JHR is targeted by several synthetic agonists that serve as insecticides disrupting the insect endocrine system. AHR is an important regulator of human endocrine homeostasis, and it responds to environmental pollutants and endocrine disruptors. Whether AHR signaling is affected by compounds that can activate JHR has not been reported. To address this question, we screened a chemical library of 50,000 compounds to identify 93 novel JHR agonists in a reporter system based on Drosophila cells. Of these compounds, 26% modulated AHR signaling in an analogous reporter assay in a human cell line, indicating a significant overlap in the agonist repertoires of the two receptors. To explore the structural features of agonist-dependent activation of JHR and AHR, we compared the ligand-binding cavities and their interactions with selective and common ligands of AHR and GCE. Molecular dynamics modeling revealed ligand-specific as well as conserved side chains within the respective cavities. Significance of predicted interactions was supported through site-directed mutagenesis. The results have indicated that (c) 2024 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.
Trvalý link: https://hdl.handle.net/11104/0360395