The vitamin D sterol-vitamin D receptor ensemble model offers unique insights into both genomic and rapid-response signaling.
Steroid hormones serve as chemical messengers in a wide number of species and target tissues by transmitting signals that result in both genomic and nongenomic responses. Genomic responses are mediated by the formation of a ligand-receptor complex with its cognate steroid hormone nuclear receptor (NR). Nongenomic responses can be mediated at the plasma membrane by a membrane-localized NR. The focus of this Review is on the structural attributes and molecular mechanisms underlying vitamin D sterol (VDS)-vitamin D receptor (VDR) selective and stereospecific regulation of nongenomic and genomic signaling. The VDS-VDR conformational ensemble model describes how VDSs can selectively initiate or block either nongenomic or genomic biological responses by interacting with two VDR ligand-binding pockets, one kinetically favored by 1alpha,25(OH)(2)D(3) (1,25D) and the other thermodynamically favored. We describe the variables that affect the three major elements of the model: the conformational flexibility of the unliganded (apo) protein, the flexibility of the VDS, and the physicochemical selectivity of the VDR genomic pocket (VDR-GP) and alternative pocket (VDR-AP). We also discuss how these three factors collectively provide a rational explanation for the complexities of VDS regulation of cell biology and highlight the current limitations of the model.
Mizwicki
Mathew T
MT
Department of Biochemistry, University of California, Riverside, CA 92521, USA. mathew.mizwicki@ucr.edu
Norman
Anthony W
AW
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002762:Cholecalciferol / Q000737:chemistry / Q000378:metabolism*; D015894:Genome, Human / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D018167:Receptors, Calcitriol / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013261:Sterols / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
D018167:Receptors, Calcitriol; D013261:Sterols; D002762:Cholecalciferol