Monoterpenoid aryl hydrocarbon receptor allosteric antagonists protect against ultraviolet skin damage in female mice

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 () and Zdeněk Dvořák ()
Additional contact information
Karolína Ondrová: Palacký University
Iveta Zůvalová: Palacký University
Barbora Vyhlídalová: Palacký University
Kristýna Krasulová: Palacký University
Eva Miková: Palacký University
Radim Vrzal: Palacký University
Petr Nádvorník: Palacký University
Binod Nepal: Drexel University College of Medicine
Sandhya Kortagere: Drexel University College of Medicine
Martina Kopečná: Palacký University
David Kopečný: Palacký University
Marek Šebela: Palacký University
Fraydoon Rastinejad: Target Discovery Institute Nuffield Department of Medicine Research Building Brasenose College University of Oxford
Hua Pu: Target Discovery Institute Nuffield Department of Medicine Research Building Brasenose College University of Oxford
Miroslav Soural: Palacký University
Katharina Maria Rolfes: IUF-Leibniz-Research Institute for Environmental Medicine
Thomas Haarmann-Stemmann: IUF-Leibniz-Research Institute for Environmental Medicine
Hao Li: Albert Einstein College of Medicine
Sridhar Mani: Albert Einstein College of Medicine
Zdeněk Dvořák: Palacký University

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38478-6

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DOI: 10.1038/s41467-023-38478-6

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