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• W2985165088 startingPage "5174" @default.
• W2985165088 abstract "Constitutive androstane receptor (CAR) is a nuclear hormone receptor that primarily functions in sensing and metabolizing xenobiotics. The basal activity of this receptor is relatively high, and CAR is deemed active in the absence of ligand. The (over)activation can promote drug toxicity and tumor growth. Thus, therapeutic treatments seek inverse agonists to inhibit or modulate CAR activities. To advance our understanding of the regulatory mechanisms of CAR, we used computational and experimental approaches to elucidate three aspects of CAR activation and inactivation: (1) ligand-dependent actions, (2) ligand-orthologue specificity, and (3) constitutive activity. For ligand-dependent actions, we examined the ligand-bound simulations and identified two sets of ligand-induced contacts promoting CAR activation via coactivator binding (H11–H12 contact) or inactivation via corepressor binding (H4–H11 contact). For orthologue specificity, we addressed a puzzling fact that murine CAR (mCAR) and human CAR (hCAR) respond differently to the same ligand (CITCO), despite their high sequence homology. We found that the helix H7 of hCAR is responsible for a stronger binding of the ligand CITCO compared to mCAR, hence a stronger CITCO-induced activation. For basal activity, we reported computer-generated unliganded CAR structures and critical mutagenesis (mCAR’s V209A and N333D) results of a cell-based transcription assay. Our results reveal that the basal conformation of CAR shares prominent features with the agonist-bound form, and helix HX has an important contribution to the constitutive activity. These findings altogether can be useful for the understanding of constitutively active receptors and the design of drug molecules targeting them." @default.
• W2985165088 created "2019-11-22" @default.
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• W2985165088 date "2019-11-12" @default.
• W2985165088 modified "2023-10-14" @default.
• W2985165088 title "Regulatory Mechanics of Constitutive Androstane Receptors: Basal and Ligand-Directed Actions" @default.
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• W2985165088 doi "https://doi.org/10.1021/acs.jcim.9b00695" @default.
• W2985165088 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/31714771" @default.
• W2985165088 hasPublicationYear "2019" @default.
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