Regulatory Mechanics of Constitutive Androstane Receptor: Basal and Ligand-directed Actions

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-ortholog 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 co-activator binding (H11-H12 contact) or inactivation via co-repressor binding (H4-H11 contact). For ortholog specificity, we addressed a puzzling fact that murine CAR (mCAR) and human CAR (hCAR) re...