Journal article
Monoterpenoid aryl hydrocarbon receptor allosteric antagonists protect against ultraviolet skin damage in female mice
NATURE COMMUNICATIONS, v 14(1), 2728
11 May 2023
PMID: 37169746
Featured in Collection : UN Sustainable Development Goals @ Drexel
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. The aryl hydrocarbon receptor regulates the expression of genes involved in many cell processes and its dysregulation has been implicated in different diseases. Here, the authors identify dietary monoterpenoid carvone as an atypical non-competitive antagonist of human aryl hydrocarbon receptor and demonstrate that it can protect against ultraviolet skin damage in female mice.
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Details
- Title
- Monoterpenoid aryl hydrocarbon receptor allosteric antagonists protect against ultraviolet skin damage in female mice
- Publication Details
- NATURE COMMUNICATIONS, v 14(1), 2728
- Publisher
- NATURE PORTFOLIO; BERLIN
- Grant note
- Financial support from the Czech Health Research Council [NV19-05-00220] (to Z.D.), the Czech Science Foundation [23-04662S] (to Z.D.), the National research council at the National Academies of Science and Pittsburgh supercomputing facility for use of Anton2 with grant [MCB210021P] (to S.K), and the Juergen Manchot Foundation (to K.M.R.) are acknowledged. We thank Dr. Radka Koncitikova for assistance with the microscale thermophoresis experiments and Dr. David Vanda for support with the synthesis of azidocarvone.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Drexel University
- Web of Science ID
- WOS:000992465700020
- Scopus ID
- 2-s2.0-85159739216
- Other Identifier
- 991021861284304721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology