A perspective on how the Vitamin D sterol/Vitamin D receptor (VDR) conformational ensemble model can potentially be used to understand the structure–function results of A-ring modified Vitamin D sterols

摘要: The steroid hormone 1alpha,25(OH)(2)-Vitamin D(3) (1,25D) activates both genomic and non-genomic intracellular signaling cascades. It is also well recognized that co-incubation of 1,25D with its C-1 epimer, 1beta,25D (HL), suppresses the efficiency signal activated by alone C-3 3alpha-1,25D (HJ) nearly as potent in suppressing PTH secretion, believed to be propagated 1,25D's signaling. Both these sterols lack hypercalcemic effect induced pharmacological doses have reduced VDR affinity compared 1,25D, measured a competition assay. Recent functional studies suggest required for Along lines we recently proposed Vitamin D sterol/VDR conformational ensemble model posits contains two distinct, yet overlapping ligand binding sites, potential differential stabilities HL pockets can used explain their different properties. region predominantly occupied sterol's A-ring when it bound either pocket (G-pocket), defined X-ray crystallography, or alternative (A-pocket), discovered using silico techniques (directed docking). Therefore, gain further insight into application this docked other diastereomer [(1beta,3alpha)=HH] 1- 3-deoxy forms (25D CF, respectively) A- G-pockets assess pockets, relative 1,25D. models were then provide putative mechanistic arguments known structure-function experimental results. This may new insights how uncouple unwanted from attractive growth inhibitory/differentiation properties do so differentially stabilizing subpopulations members.