Structural basis for the ligand-dependent activation of heterodimeric AHR-ARNT complex
Abstract The aryl hydrocarbon receptor (AHR) possesses an extraordinary capacity to sense and respond to a wide range of small-molecule ligands, ranging from polycyclic aromatic hydrocarbons to endogenous compounds. Upon ligand binding, AHR translocates from the cytoplasm to nucleus, forming a trans...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-02-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56574-7 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1823861855793184768 |
|---|---|
| author | Xiaotong Diao Qinghong Shang Mengqi Guo Yubin Huang Meina Zhang Xiaoyu Chen Yinping Liang Xiangnan Sun Fan Zhou Jingjing Zhuang Shuang-Jiang Liu Christoph F. A. Vogel Fraydoon Rastinejad Dalei Wu |
| author_facet | Xiaotong Diao Qinghong Shang Mengqi Guo Yubin Huang Meina Zhang Xiaoyu Chen Yinping Liang Xiangnan Sun Fan Zhou Jingjing Zhuang Shuang-Jiang Liu Christoph F. A. Vogel Fraydoon Rastinejad Dalei Wu |
| author_sort | Xiaotong Diao |
| collection | DOAJ |
| description | Abstract The aryl hydrocarbon receptor (AHR) possesses an extraordinary capacity to sense and respond to a wide range of small-molecule ligands, ranging from polycyclic aromatic hydrocarbons to endogenous compounds. Upon ligand binding, AHR translocates from the cytoplasm to nucleus, forming a transcriptionally active complex with aryl hydrocarbon receptor nuclear translocator (ARNT), for DNA binding and initiation of gene expression programs that include cellular detoxification pathways and immune responses. Here, we examine the molecular mechanisms governing AHR’s high-affinity binding and activation by a diverse group of ligands. Crystal structures of the AHR-ARNT-DNA complexes, bound with each of six established AHR ligands, including Tapinarof, 6-formylindolo[3,2-b]carbazole (FICZ), benzo[a]pyrene (BaP), β-naphthoflavone (BNF), Indigo and Indirubin, reveal an unconventional mode of subunit assembly with intimate association between the PAS-B domains of AHR and ARNT. AHR’s PAS-B domain utilizes eight conserved residues whose dynamic rearrangements account for the ability to bind to ligands through hydrophobic and π-π interactions. Our findings further reveal the structural underpinnings of a ligand-driven activation mechanism, whereby a segment of the AHR protein undergoes a structural transition from chaperone engagement to ARNT heterodimer stabilization, to generate the transcriptionally competent assembly. Our results provide key information for the future development of AHR-targeting drugs. |
| format | Article |
| id | doaj-art-f64556cc85fe4ff8914c72054416538e |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-f64556cc85fe4ff8914c72054416538e2025-02-09T12:45:03ZengNature PortfolioNature Communications2041-17232025-02-0116111410.1038/s41467-025-56574-7Structural basis for the ligand-dependent activation of heterodimeric AHR-ARNT complexXiaotong Diao0Qinghong Shang1Mengqi Guo2Yubin Huang3Meina Zhang4Xiaoyu Chen5Yinping Liang6Xiangnan Sun7Fan Zhou8Jingjing Zhuang9Shuang-Jiang Liu10Christoph F. A. Vogel11Fraydoon Rastinejad12Dalei Wu13State Key Laboratory of Microbial Technology, Shandong UniversityState Key Laboratory of Microbial Technology, Shandong UniversityState Key Laboratory of Microbial Technology, Shandong UniversityState Key Laboratory of Microbial Technology, Shandong UniversityState Key Laboratory of Microbial Technology, Shandong UniversityState Key Laboratory of Microbial Technology, Shandong UniversityState Key Laboratory of Microbial Technology, Shandong UniversityState Key Laboratory of Microbial Technology, Shandong UniversityShanghai Zelixir BiotechState Key Laboratory of Microbial Technology, Shandong UniversityState Key Laboratory of Microbial Technology, Shandong UniversityCenter for Health and the Environment, University of California, One Shields AvenueTarget Discovery Institute, NDM Research Building, University of Oxford, Old Road CampusState Key Laboratory of Microbial Technology, Shandong UniversityAbstract The aryl hydrocarbon receptor (AHR) possesses an extraordinary capacity to sense and respond to a wide range of small-molecule ligands, ranging from polycyclic aromatic hydrocarbons to endogenous compounds. Upon ligand binding, AHR translocates from the cytoplasm to nucleus, forming a transcriptionally active complex with aryl hydrocarbon receptor nuclear translocator (ARNT), for DNA binding and initiation of gene expression programs that include cellular detoxification pathways and immune responses. Here, we examine the molecular mechanisms governing AHR’s high-affinity binding and activation by a diverse group of ligands. Crystal structures of the AHR-ARNT-DNA complexes, bound with each of six established AHR ligands, including Tapinarof, 6-formylindolo[3,2-b]carbazole (FICZ), benzo[a]pyrene (BaP), β-naphthoflavone (BNF), Indigo and Indirubin, reveal an unconventional mode of subunit assembly with intimate association between the PAS-B domains of AHR and ARNT. AHR’s PAS-B domain utilizes eight conserved residues whose dynamic rearrangements account for the ability to bind to ligands through hydrophobic and π-π interactions. Our findings further reveal the structural underpinnings of a ligand-driven activation mechanism, whereby a segment of the AHR protein undergoes a structural transition from chaperone engagement to ARNT heterodimer stabilization, to generate the transcriptionally competent assembly. Our results provide key information for the future development of AHR-targeting drugs.https://doi.org/10.1038/s41467-025-56574-7 |
| spellingShingle | Xiaotong Diao Qinghong Shang Mengqi Guo Yubin Huang Meina Zhang Xiaoyu Chen Yinping Liang Xiangnan Sun Fan Zhou Jingjing Zhuang Shuang-Jiang Liu Christoph F. A. Vogel Fraydoon Rastinejad Dalei Wu Structural basis for the ligand-dependent activation of heterodimeric AHR-ARNT complex Nature Communications |
| title | Structural basis for the ligand-dependent activation of heterodimeric AHR-ARNT complex |
| title_full | Structural basis for the ligand-dependent activation of heterodimeric AHR-ARNT complex |
| title_fullStr | Structural basis for the ligand-dependent activation of heterodimeric AHR-ARNT complex |
| title_full_unstemmed | Structural basis for the ligand-dependent activation of heterodimeric AHR-ARNT complex |
| title_short | Structural basis for the ligand-dependent activation of heterodimeric AHR-ARNT complex |
| title_sort | structural basis for the ligand dependent activation of heterodimeric ahr arnt complex |
| url | https://doi.org/10.1038/s41467-025-56574-7 |
| work_keys_str_mv | AT xiaotongdiao structuralbasisfortheliganddependentactivationofheterodimericahrarntcomplex AT qinghongshang structuralbasisfortheliganddependentactivationofheterodimericahrarntcomplex AT mengqiguo structuralbasisfortheliganddependentactivationofheterodimericahrarntcomplex AT yubinhuang structuralbasisfortheliganddependentactivationofheterodimericahrarntcomplex AT meinazhang structuralbasisfortheliganddependentactivationofheterodimericahrarntcomplex AT xiaoyuchen structuralbasisfortheliganddependentactivationofheterodimericahrarntcomplex AT yinpingliang structuralbasisfortheliganddependentactivationofheterodimericahrarntcomplex AT xiangnansun structuralbasisfortheliganddependentactivationofheterodimericahrarntcomplex AT fanzhou structuralbasisfortheliganddependentactivationofheterodimericahrarntcomplex AT jingjingzhuang structuralbasisfortheliganddependentactivationofheterodimericahrarntcomplex AT shuangjiangliu structuralbasisfortheliganddependentactivationofheterodimericahrarntcomplex AT christophfavogel structuralbasisfortheliganddependentactivationofheterodimericahrarntcomplex AT fraydoonrastinejad structuralbasisfortheliganddependentactivationofheterodimericahrarntcomplex AT daleiwu structuralbasisfortheliganddependentactivationofheterodimericahrarntcomplex |