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.

Department of Biochemistry Faculty of Science Palacký University Olomouc Czech Republic

Department of Cell Biology and Genetics Faculty of Science Palacký University Olomouc Czech Republic

Department of Experimental Biology Faculty of Science Palacký University Olomouc Czech Republic

Department of Medicine Oncology Molecular Pharmacology and Genetics Albert Einstein College of Medicine Bronx NY USA

Department of Microbiology and Immunology Drexel University College of Medicine Philadelphia PA USA

Department of Organic Chemistry Faculty of Science Palacký University Olomouc Czech Republic

IUF Leibniz Research Institute for Environmental Medicine Düsseldorf Germany

Target Discovery Institute Nuffield Department of Medicine Research Building Brasenose College University of Oxford Oxford UK

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Jasmone Is a Ligand-Selective Allosteric Antagonist of Aryl Hydrocarbon Receptor (AhR)