5nj8
From Proteopedia
Structural basis for aryl hydrocarbon receptor mediated gene activation
Structural highlights
FunctionAHR_HUMAN Ligand-activated transcriptional activator. Binds to the XRE promoter region of genes it activates. Activates the expression of multiple phase I and II xenobiotic chemical metabolizing enzyme genes (such as the CYP1A1 gene). Mediates biochemical and toxic effects of halogenated aromatic hydrocarbons. Involved in cell-cycle regulation. Likely to play an important role in the development and maturation of many tissues. Regulates the circadian clock by inhibiting the basal and circadian expression of the core circadian component PER1. Inhibits PER1 by repressing the CLOCK-ARNTL/BMAL1 heterodimer mediated transcriptional activation of PER1.[1] [2] Publication Abstract from PubMedThe 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. Structural Basis for Aryl Hydrocarbon Receptor-Mediated Gene Activation.,Schulte KW, Green E, Wilz A, Platten M, Daumke O Structure. 2017 Jul 5;25(7):1025-1033.e3. doi: 10.1016/j.str.2017.05.008. Epub, 2017 Jun 9. PMID:28602820[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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