title: Constitutive activity and ligand-dependent activation of the nuclear receptor CAR-insights from molecular dynamics simulations.
abstract: The constitutive androstane receptor (CAR) possesses, unlike most other nuclear receptors, a pronounced basal activity in vitro whose structural basis is still not fully understood. Using comparative molecular dynamics simulations of CAR X-ray crystal structures, we evaluated the molecular basis for constitutive activity and ligand-dependent receptor activation. Our results suggest that a combination of van der Waals interactions and hydrogen bonds is required to maintain the activation helix in the active conformation also in absence of a ligand. Furthermore, we identified conformational rearrangements within the ligand-binding pocket upon agonist binding and an influence of CAR inducers pregnanedione and CITCO on the helical conformation of the activation helix. Based on the results a model for ligand-dependent CAR activation is suggested.
authors.affiliation: Faculty of Health Sciences/School of Pharmacy, University of Eastern Finland, P.O. Box 1627, Kuopio 70211, Finland. windshuegel@zbh.uni-hamburg.de
authors.forename: Björn
authors.initials: B
authors.lastname: Windshügel
authors.forename: Antti
authors.initials: A
authors.lastname: Poso
mesh_terms: D000090702:Constitutive Androstane Receptor; D018360:Crystallography, X-Ray; D006801:Humans; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D000090702:Constitutive Androstane Receptor; D018160:Receptors, Cytoplasmic and Nuclear