Structural Basis for Aryl Hydrocarbon Receptor-Mediated Gene Activation
| Autor: | Kathrin Wiebke Schulte, Edward W. Green, Michael Platten, Annabel Wilz, Oliver Daumke |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Aryl hydrocarbon receptor nuclear translocator Cellular homeostasis Endogeny Biology Xenobiotics 03 medical and health sciences chemistry.chemical_compound Structural Biology Transcription (biology) Humans Molecular Biology Transcription factor Regulation of gene expression Binding Sites Aryl Hydrocarbon Receptor Nuclear Translocator DNA respiratory system Aryl hydrocarbon receptor respiratory tract diseases Molecular Docking Simulation HEK293 Cells 030104 developmental biology Receptors Aryl Hydrocarbon chemistry Biochemistry biology.protein Protein Multimerization Protein Binding |
| Zdroj: | Structure. 25:1025-1033.e3 |
| ISSN: | 0969-2126 |
| DOI: | 10.1016/j.str.2017.05.008 |
| Popis: | The aryl hydrocarbon receptor (AHR) and the AHR nuclear translocator (ARNT) constitute a heterodimeric basic helix-loop-helix-Per-ARNT-Sim (bHLH-PAS) domain containing transcription factor with central functions in development and cellular homeostasis. AHR is activated by xenobiotics, notably dioxin, as well as by exogenous and endogenous metabolites. Modulation of AHR activity holds promise for the treatment of diseases featuring altered cellular homeostasis, such as cancer or autoimmune disorders. Here, we present the crystal structure of a heterodimeric AHR:ARNT complex containing the PAS A and bHLH domain bound to its target DNA. The structure provides insights into the DNA binding mode of AHR and elucidates how stable dimerization of AHR:ARNT is achieved through sophisticated domain interplay via three specific interfaces. Using mutational analyses, we prove the relevance of the observed interfaces for AHR-mediated gene activation. Thus, our work establishes the structural basis of AHR assembly and DNA interaction and provides a template for targeted drug design. |
| Databáze: | OpenAIRE |
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