Monoterpenoid aryl hydrocarbon receptor allosteric antagonists protect against ultraviolet skin damage in female mice
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 antagon...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-38478-6 |
| _version_ | 1797827427173400576 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Karolína Ondrová |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T12:48:07Z |
| format | Article |
| id | doaj.art-269654521e354a11b792e6976398f868 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-09T12:48:07Z |
| publishDate | 2023-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-269654521e354a11b792e6976398f8682023-05-14T11:21:51ZengNature PortfolioNature Communications2041-17232023-05-0114111510.1038/s41467-023-38478-6Monoterpenoid aryl hydrocarbon receptor allosteric antagonists protect against ultraviolet skin damage in female miceKarolína Ondrová0Iveta Zůvalová1Barbora Vyhlídalová2Kristýna Krasulová3Eva Miková4Radim Vrzal5Petr Nádvorník6Binod Nepal7Sandhya Kortagere8Martina Kopečná9David Kopečný10Marek Šebela11Fraydoon Rastinejad12Hua Pu13Miroslav Soural14Katharina Maria Rolfes15Thomas Haarmann-Stemmann16Hao Li17Sridhar Mani18Zdeněk Dvořák19Department of Cell Biology and Genetics, Faculty of Science, Palacký UniversityDepartment of Cell Biology and Genetics, Faculty of Science, Palacký UniversityDepartment of Cell Biology and Genetics, Faculty of Science, Palacký UniversityDepartment of Cell Biology and Genetics, Faculty of Science, Palacký UniversityDepartment of Cell Biology and Genetics, Faculty of Science, Palacký UniversityDepartment of Cell Biology and Genetics, Faculty of Science, Palacký UniversityDepartment of Cell Biology and Genetics, Faculty of Science, Palacký UniversityDepartment of Microbiology & Immunology, Drexel University College of MedicineDepartment of Microbiology & Immunology, Drexel University College of MedicineDepartment of Experimental Biology, Faculty of Science, Palacký UniversityDepartment of Experimental Biology, Faculty of Science, Palacký UniversityDepartment of Biochemistry, Faculty of Science, Palacký UniversityTarget Discovery Institute Nuffield Department of Medicine Research Building Brasenose College University of OxfordTarget Discovery Institute Nuffield Department of Medicine Research Building Brasenose College University of OxfordDepartment of Organic Chemistry, Faculty of Science, Palacký UniversityIUF-Leibniz-Research Institute for Environmental MedicineIUF-Leibniz-Research Institute for Environmental MedicineDepartment of Medicine, Oncology, Molecular Pharmacology, and Genetics, Albert Einstein College of MedicineDepartment of Medicine, Oncology, Molecular Pharmacology, and Genetics, Albert Einstein College of MedicineDepartment of Cell Biology and Genetics, Faculty of Science, Palacký UniversityAbstract 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.https://doi.org/10.1038/s41467-023-38478-6 |
| spellingShingle | 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 Monoterpenoid aryl hydrocarbon receptor allosteric antagonists protect against ultraviolet skin damage in female mice Nature Communications |
| title | Monoterpenoid aryl hydrocarbon receptor allosteric antagonists protect against ultraviolet skin damage in female mice |
| title_full | Monoterpenoid aryl hydrocarbon receptor allosteric antagonists protect against ultraviolet skin damage in female mice |
| title_fullStr | Monoterpenoid aryl hydrocarbon receptor allosteric antagonists protect against ultraviolet skin damage in female mice |
| title_full_unstemmed | Monoterpenoid aryl hydrocarbon receptor allosteric antagonists protect against ultraviolet skin damage in female mice |
| title_short | Monoterpenoid aryl hydrocarbon receptor allosteric antagonists protect against ultraviolet skin damage in female mice |
| title_sort | monoterpenoid aryl hydrocarbon receptor allosteric antagonists protect against ultraviolet skin damage in female mice |
| url | https://doi.org/10.1038/s41467-023-38478-6 |
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