TY - JOUR
T1 - Monoterpenoid aryl hydrocarbon receptor allosteric antagonists protect against ultraviolet skin damage in female mice
AU - Ondrová, Karolína
AU - Zůvalová, Iveta
AU - Vyhlídalová, Barbora
AU - Krasulová, Kristýna
AU - Miková, Eva
AU - Vrzal, Radim
AU - Nádvorník, Petr
AU - Nepal, Binod
AU - Kortagere, Sandhya
AU - Kopečná, Martina
AU - Kopečný, David
AU - Šebela, Marek
AU - Rastinejad, Fraydoon
AU - Pu, Hua
AU - Soural, Miroslav
AU - Rolfes, Katharina Maria
AU - Haarmann-Stemmann, Thomas
AU - Li, Hao
AU - Mani, Sridhar
AU - Dvořák, Zdeněk
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-023-38478-6
DO - 10.1038/s41467-023-38478-6
M3 - Article
C2 - 37169746
AN - SCOPUS:85159739216
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2728
ER -