| Autor: |
Karolína Ondrová, Iveta Zůvalová, Barbora Vyhlídalová, Kristýna Krasulová, Eva Miková, Radim Vrzal, Petr Nádvorník, Binod Nepal, Sandhya Kortagere, Martina Kopečná, David Kopečný, Marek Šebela, Fraydoon Rastinejad, Hua Pu, Miroslav Soural, Katharina Maria Rolfes, Thomas Haarmann-Stemmann, Hao Li, Sridhar Mani, Zdeněk Dvořák |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
|
| Zdroj: |
Nature Communications, Vol 14, Iss 1, Pp 1-15 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2041-1723 |
| DOI: |
10.1038/s41467-023-38478-6 |
| Popis: |
Abstract The human aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is a pivotal regulator of human physiology and pathophysiology. Allosteric inhibition of AhR was previously thought to be untenable. Here, we identify carvones as noncompetitive, insurmountable antagonists of AhR and characterize the structural and functional consequences of their binding. Carvones do not displace radiolabeled ligands from binding to AhR but instead bind allosterically within the bHLH/PAS-A region of AhR. Carvones do not influence the translocation of ligand-activated AhR into the nucleus but inhibit the heterodimerization of AhR with its canonical partner ARNT and subsequent binding of AhR to the promoter of CYP1A1. As a proof of concept, we demonstrate physiologically relevant Ahr-antagonism by carvones in vivo in female mice. These substances establish the molecular basis for selective targeting of AhR regardless of the type of ligand(s) present and provide opportunities for the treatment of disease processes modified by AhR. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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